Oral pharmaceutical dosage forms

ABSTRACT

Abuse-resistant oral dosage forms suitable for administration of pharmacologically active agents are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/786,218,filed Mar. 5, 2013, which application is a continuation of applicationSer. No. 12/315,868, filed Dec. 5, 2008, now U.S. Pat. No. 8,415,401,issued Apr. 9, 2013, which application claims the benefit of U.S.Provisional Application Ser. No. 61/005,681 filed Dec. 6, 2007, U.S.Provisional Application Ser. No. 61/005,685 filed Dec. 6, 2007, and U.S.Provisional Application Ser. No. 61/198,201, filed Nov. 3, 2008, all ofwhich applications are fully incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to oral pharmaceutical dosage forms and the usethereof. More specifically, this invention relates to abuse-resistantoral pharmaceutical dosage forms and their use to deliverpharmacologically active agents.

BACKGROUND

Techniques and compositions for drug delivery of pharmaceuticals,including oral delivery, are well known. For example antihistamines,decongestants and antacids are all commonly delivered in solid tabletform. Analgesics have been delivered orally in tablet form for manyyears, for example salicylic acid, morphine, Demerol™ (meperidine),codeine and Percocet™ (oxycodone). Controlled release and sustainedrelease pharmaceutical compositions have also been available for manyyears; for example the Contac 400 Time Capsule™ (PhenylpropanolamineHydrochloride and Chlorpheniramine Maleate), anti-psychotics, melatoninformulations provide release of an active agent over several hours.Analgesics are of particular interest for controlled releaseformulations, and common controlled release formulations for analgesicsinclude the OxyContin® (oxycodone), MS Contin™ (morphine), CS Contin™(codeine).

Formulation of drugs for delivery, particularly oral delivery, posescertain challenges. One challenge is to produce an oralcontrolled-release dosage form that provides for a relatively steadydose of drug over the approximately eight hours during which the dosageform passes through the gastrointestinal tract. Sustained release isoften achieved by providing the tablet with a coating that delaysrelease, or by formulating the tablet in such a way that itdisintegrates relatively slowly, releasing drug as it does so. A tablet,however, once ingested, is subject to considerable mechanical andchemical stresses as it passes through the esophagus, stomach, duodenum,jejunum, ileum, large intestine and colon, thus providing a significantchallenge in maintaining controlled release of the drug formulation.Acids, enzymes and peristalsis can cause the tablet to break apart,resulting in exposure of the inside of the tablet and an increase insurface area of the tablet material. This will tend to increase thedelivery rate of the drug or otherwise adversely affect the controlledrelease properties of the dosage form.

Another challenge, is to produce a dosage form, including an oral dosageform, that reduces the potential for drug abuse. In particular, opioids,CNS-depressants, and stimulants are commonly abused. According to a 1999study by the National Institute on Drug Abuse (NIDA), an estimated 4million people, about 2 percent of the population age 12 and older, were(at the time of the study) using prescription drugs “non-medically.” Ofthese, 2.6 million misused pain relievers, 1.3 million misused sedativesand tranquilizers, and 0.9 million misused stimulants.

While many prescription drugs can be abused, the most common classes ofabused drugs are: (1) Opioids—often prescribed to treat pain, (2) CNSDepressants—used to treat anxiety and sleep disorders, and (3)Stimulants—prescribed to treat narcolepsy and attentiondeficit/hyperactivity disorder.

Opioids are a class of potent narcotics that includes, for example,morphine, codeine, oxycodone and fentanyl and related drugs. Morphine isoften used to alleviate severe pain. Codeine is used for milder pain.Other examples of opioids that can be prescribed to alleviate paininclude oxycodone (e.g. OxyContin®—an oral, controlled release form ofthe drug); propoxyphene (e.g. Darvon™); hydrocodone (e.g. Vicodin™);hydromorphone (e.g. Dilaudid™); and meperidine (e.g. Demerol™).

In addition to relieving pain, opioids can also produce a sensation ofeuphoria, and when taken in large doses, can cause severe respiratorydepression which can be fatal.

CNS depressants slow down normal brain function by increasing GABAactivity, thereby producing a drowsy or calming effect. In higher doses,some CNS depressants can become general anesthetics, and in very highdoses may cause respiratory failure and death. CNS depressants arefrequently abused, and often the abuse of CNS depressants occurs inconjunction with the abuse of another substance or drug, such as alcoholor cocaine. Many deaths occur yearly through such drug abuse. CNSdepressants can be divided into two groups, based on their chemistry andpharmacology: (1) Barbiturates, such as mephobarbital (e.g. Mebaral™)and pentobarbital sodium (e.g. Nembutal™), which are used to treatanxiety, tension, and sleep disorders. (2) Benzodiazepines, such asdiazepam (e.g. Valium™) chlordiazepoxide HCl (e.g. Librium™), andalprazolam (e.g. Xanax™), which can be prescribed to treat anxiety,acute stress reactions, and panic attacks. Benzodiazepines that have amore sedating effect, such as triazolam (e.g. Halcion™) and estazolam(e.g. ProSom™) can be prescribed for short-term treatment of sleepdisorders.

Stimulants are a class of drugs that enhance brain activity—they causean increase in alertness, attention, and energy that is accompanied byincreases in blood pressure, heart rate, and respiration. Stimulants arefrequently prescribed for treating narcolepsy, attention-deficithyperactivity disorder (ADHD), and depression. Stimulants may also beused for short-term treatment of obesity, and for patients with asthma.Stimulants such as dextroamphetamine (Dexedrine™) and methylphenidate(Ritalin™) have chemical structures that are similar to key brainneurotransmitters called monoamines, which include norepinephrine anddopamine. Stimulants increase the levels of these chemicals in the brainand body. This, in turn, increases blood pressure and heart rate,constricts blood vessels, increases blood glucose, and opens up thepathways of the respiratory system. In addition, the increase indopamine is associated with a sense of euphoria that can accompany theuse of these drugs.

Taking high doses of a stimulant can result in an irregular heartbeat,dangerously high body temperatures, and/or the potential forcardiovascular failure or lethal seizures. Taking high doses of somestimulants repeatedly over a short period of time can lead to hostilityor feelings of paranoia in some individuals.

A common and particularly dangerous cocktail of drugs is produced whenstimulants are mixed with antidepressants or over-the-counter coldmedicines containing decongestants. Anti-depressants may enhance theeffects of a stimulant, and stimulants in combination with decongestantsmay cause blood pressure to become dangerously high or lead to irregularheart rhythms, which in extreme cases may be fatal.

Solid dosage forms are particularly susceptible to abuse. For example,tablets for oral drug delivery can be ground down into a powder. Drugaddicts and abusers grind down the tablet in order to nasally inhale thedrug. Addicts also grind the tablet to extract the drug into alcohol orwater to make a concentrated injectable drug solution. Administration ofvarious abused drugs in this way produces a sudden high dose of druginto the blood stream making the user euphoric. These well-knowntechniques for drug abuse have been used for many years with all mannerof drugs.

One particularly important example of a highly addictive drug that iscommonly abused by crushing (for nasal inhalation), and/or alcohol orwater extraction (for intravenous injection) is Oxycodone. Oxycodone isa powerful analgesic that is available in an extended release tabletform (OxyContin®, Purdue Pharmaceuticals) and is manufactured in 10 mg,20 mg, 40 mg, and 80 mg tablet strengths (the 160 mg tablet strength hasbeen withdrawn from the US market due to prevalence of abuse of thisparticular product strength and the associated hazard from abuse of sucha high dose of oxycodone. The OxyContin® tablets are formulated astime-release tablets (about 12 hours of release), but of course crushingand grinding the tablet destroys its controlled-release properties. In2004, oxycodone abuse resulted in 36,600 visits to US emergency rooms,20,000 of which are known to stem from abuse of sustained-releaseoxycodone formulations (e.g., OxyContin® tablets). Intentional abuse ofoxycodone has reached epidemic proportions in the US, where, accordingto a 2004 National Survey on Drug Use and Health, 3.1 million Americanshave used sustained-release oxycodone for non-medical purposes.Furthermore, unintentional overdose deaths from opioid analgesics haveincreased over 18% per year from 1990 to 2002, at which time opioidanalgesic poisoning was listed in 5528 death certificates, more thaneither heroin or cocaine. Chewing/snorting a crushed 40 mg OxyContin® islike taking eight Percocet™ at once or an 80 mg OxyContin® is liketaking 16 Percocet™ all at once. Overdose produces small pupils, slowbreathing, dizziness, weakness, seizures, loss of consciousness, coma,and sometimes death.

SUMMARY OF THE INVENTION

Abuse-resistant oral pharmaceutical dosage forms that include apharmacologically active agent and a controlled release carrier systemare provided. It is thus an object of the present invention to providean oral pharmaceutical dosage form that includes a pharmacologicallyactive agent and a controlled release carrier system, where thecontrolled release carrier system includes a High Viscosity LiquidCarrier Material (“HVLCM”), a network former, a rheology modifier, ahydrophilic agent and a solvent. It is also an object of the presentinvention to provide the above-described dosage forms wherein the invivo absorption of the active agent from the dosage form is enhancedupon administration of the dosage form with food, or, conversely,wherein in vivo release of the active agent from the controlled releasecarrier system is substantially free from food effect. It is a relatedobject of the invention to provide the above-described dosage formswhere the controlled release carrier system further provides a decreasedrisk of misuse or abuse, for example where such decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the active agent from the dosage form and/or by the absence of anysignificant effect on absorption of the active agent from the dosageform upon co-ingestion of the dosage form and alcohol by a subject. Ineach of the above-described related objects of the invention, thecontrolled release carrier system can be further characterized by aunique set of pharmaceutical excipients including certain combinationsof solvents, viscosity enhancing agents, and the like. The controlledrelease carrier system provides abuse-resistant properties to the dosageform. It is accordingly a related object of the invention to provide theabove-described dosage form wherein the controlled release carriersystem also includes one or more of the following additional components:a viscosity enhancing agent; and a stabilizing agent. In particularembodiments, the HVLCM can comprise sucrose acetate isobutyrate (“SAM”);the network former can comprise cellulose acetate butyrate (“CAB”),cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethylcellulose or cellulose triacetate; the rheology modifier can compriseisopropyl myristate (“IPM”), caprylic/capric triglyceride, ethyl oleate,triethyl citrate, dimethyl phthalate or benzyl benzoate; the hydrophilicagent can comprise hydroxyethylcellulose (“HEC”),hydroxypropylcellulose, caboxymethylcellulose, polyethylene glycol orpolyvinylpyrrolidone; and the solvent can comprise triacetin,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,propylene carbonate or glycofurol. In addition, the viscosity enhancingagent can comprise a silicon dioxide, and the stabilizer can comprisebutylhydroxyl toluene (“BHT”). In certain preferred embodiments, theactive agent can be an opioid, CNS-depressant, or CNS-stimulant that hasa particularly high potential for abuse, diversion or other misuse.Preferably, the active agent can comprise an opioid, an amphetamine, ora methylphenidate, in each case either as a salt or as a free base.

It is another object of the invention to provide an oral pharmaceuticaldosage form that includes a pharmacologically active agent and acontrolled release carrier system. The controlled release carrier systemincludes a High Viscosity Liquid Carrier Material (“HVLCM”), a networkformer and at least one viscosity enhancing agent, a hydrophiliccolvent, and a hydrophobic solvent. It is also an object of the presentinvention to provide the above-described dosage forms wherein the invivo absorption of the active agent from the dosage form is enhancedupon administration of the dosage form with food, or, conversely,wherein in vivo release of the active agent from the controlled releasecarrier system is substantially free from food effect. It is a relatedobject of the invention to provide the above-described dosage formswhere the controlled release carrier system further provides a decreasedrisk of misuse or abuse, for example where such decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the active agent from the dosage form and/or by the absence of anysignificant effect on absorption of the active agent from the dosageform upon co-ingestion of the dosage form and alcohol by a subject. Ineach of the above-described related objects of the invention, thecontrolled release carrier system can be further characterized by aunique set of pharmaceutical excipients including certain combinationsof solvents, viscosity enhancing agents, and the like. The controlledrelease carrier system provides abuse-resistant properties to the dosageform. In certain preferred embodiments, the network former can compriseCAB, cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethylcellulose or cellulose triacetate; the first viscosity enhancing agentcan comprise HEC, hydroxypropylcellulose, carboxymethylcellulose,polyethylene glycol or polyvinylpyrrolidone; the hydrophilic solvent cancomprise triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone,dimethylsulfoxide, ethyl lactate, propylene carbonate or glycofurol; andthe hydrophobic solvent can comprise IPM. In addition, the active agentcan be an opioid, CNS-depressant, or CNS-stimulant that has aparticularly high potential for abuse, diversion or other misuse.Preferably, the active agent can comprise an opioid, an amphetamine, ora methylphenidate, in each case either as a salt or as a free base.

It is another object of the invention to provide a process for thepreparation of an oral pharmaceutical dosage form that includes apharmacologically active agent and a controlled release carrier system,where the controlled release carrier system includes a High ViscosityLiquid Carrier Material (“HVLCM”), a network former, a rheologymodifier, a hydrophilic agent and a solvent. The manufacturing orcompounding process includes the steps of: preheating the HVLCM; mixingthe solvent with the preheated HVLCM to form a uniform solution of theHVLCM in the solvent; dispersing the network former in the solution todissolve the network former in the solution; mixing from 5 to 30% of therheology modifier or, optionally, a solution of a stabilising agent andfrom 5 to 30% of the rheology modifier with the formulation; add andmixing the pharmacologically active agent; adding and mixing thehydrophilic agent; and, optionally, adding and mixing a viscosityenhancing agent, and adding and the balance of the rheology modifier.Furthermore, the process can include the step of filling capsules withthe formulation obtained in the process and, optionally, packaging thefilled capsules into unit dose blisters or multidose plastic bottles. Itis a related object of the invention to provide a process for thepreparation of an oral pharmaceutical dosage form that includes apharmacologically active agent and a controlled release carrier system,where the controlled release carrier system includes a HVLCM, a networkformer, a rheology modifier, a hydrophilic agent and a solvent. Themanufacturing or compounding process includes the steps of: preheatingthe HVLCM; mixing the solvent with the preheated HVLCM to form a uniformsolution of the HVLCM in the solvent; optionally, mixing a solution of astabilising agent and from 5 to 30% of the rheology modifier with thesolution obtained in preceeding step; adding and mixing the rheologymodifier or, if step the balance of the rheology modifier with thesolution obtained in the earlier step; optionally, adding and mixing aviscosity enhancing agent with the formulation obtained in thepreceeding step; adding and dispersing the network former into thesolution thus obtained, thereby dissolving the network former in thesolution; adding and mixing the pharmacologically active agent with theformulation obtained in the previous step; adding and mixing thehydrophilic agent. Furthermore, the process can include the step offilling capsules with the formulation obtained in the process and,optionally, packaging the filled capsules into unit dose blisters ormultidose plastic bottles. It is a related object of the presentinvention to provide an oral pharmaceutical dosage form that isobtainable by the above manufacturing or compounding processes.

It is another object of the invention to provide a process for thepreparation of an oral pharmaceutical dosage form that includes apharmacologically active agent and a controlled release carrier system,where the controlled release carrier system includes a HVLCM, a networkformer, a first viscosity enhancing agent, a hydrophilic solvent and ahydrophobic solvent. The manufacturing or compounding process includesthe steps of: preheating the HVLCM; mixing the solvent with thepreheated HVLCM to form a uniform solution of the HVLCM in the solvent;dispersing the network former in the solution to dissolve the networkformer in the solution; mixing from 5 to 30% of the rheology modifieror, optionally, a solution of a stabilising agent and from 5 to 30% ofthe rheology modifier with the formulation; add and mixing thepharmacologically active agent; adding and mixing the hydrophilic agent;and, optionally, adding and mixing a viscosity enhancing agent, andadding and the balance of the rheology modifier. Furthermore, theprocess can include the step of filling capsules with the formulationobtained in the process and, optionally, packaging the filled capsulesinto unit dose blisters or multidose plastic bottles. It is a relatedobject of the invention to provide a process for the preparation of anoral pharmaceutical dosage form that includes a pharmacologically activeagent and a controlled release carrier system, where the controlledrelease carrier system includes a HVLCM, a network former, a firstviscosity enhancing agent, a hydrophilic solvent and a hydrophobicsolvent. The manufacturing or compounding process includes the steps of:preheating the HVLCM; mixing the solvent with the preheated HVLCM toform a uniform solution of the HVLCM in the solvent; optionally, mixinga solution of a stabilising agent and from 5 to 30% of the rheologymodifier with the solution obtained in preceeding step; adding andmixing the rheology modifier or, if step the balance of the rheologymodifier with the solution obtained in the earlier step; optionally,adding and mixing a viscosity enhancing agent with the formulationobtained in the preceeding step; adding and dispersing the networkformer into the solution thus obtained, thereby dissolving the networkformer in the solution; adding and mixing the pharmacologically activeagent with the formulation obtained in the previous step; adding andmixing the hydrophilic agent. Furthermore, the process can include thestep of filling capsules with the formulation obtained in the processand, optionally, packaging the filled capsules into unit dose blistersor multidose plastic bottles. It is a related object of the presentinvention to provide an oral pharmaceutical dosage form that isobtainable by the above manufacturing or compounding processes.

It is a further object of the invention to provide an abuse-resistantoral pharmaceutical dosage form that includes a pharmacologically activeagent and a controlled release carrier system. The controlled releasecarrier system provides for controlled in vivo release of the agentcharacterized in that the individual steady state C_(min)/C_(max)variance within an interdose interval is less than or equal to theTherapeutic Index of the active agent. It is also an object of thepresent invention to provide an abuse-resistant oral pharmaceuticaldosage form that includes a pharmacologically active agent and acontrolled release carrier system, where the dosage form is suitable foruse in a BID-dosing regimen. It is a related object of the invention toprovide the above-described dosage forms where the in vivopharmacological performance is characterized by having individualC_(min)/C_(max) variance at steady state is less than or equal to about2 to 3 when dosed at the therapeutically effective dose or AUC. It isalso a related object of the invention to provide the above-describeddosage forms where the controlled release carrier system furtherprovides a decreased risk of misuse or abuse, for example where suchdecreased risk of misuse or abuse is characterized by a low in vitrosolvent extractability value of the active agent from the dosage formand/or by the absence of any significant effect on absorption of theactive agent from the dosage form upon co-ingestion of the dosage formand alcohol by a subject. In each of the above-described related objectsof the invention, the controlled release carrier system can be furthercharacterized by a unique set of pharmaceutical excipients includingsolvents, carrier materials, and viscosity enhancing agents. In certainpreferred embodiments, the active agent can be an opioid,CNS-depressant, or CNS-stimulant that has a particularly high potentialfor abuse, diversion or other misuse. Preferably, the active agent cancomprise an opioid, an amphetamine, or a methylphenidate, in each caseeither as a salt or as a free base.

It is a further object of the present invention to provide anabuse-resistant oral pharmaceutical dosage form that includes apharmacologically active agent and a controlled release carrier system.The controlled release carrier system provides for controlled in vivorelease of the agent characterized in that the individual steady stateC_(min)/C_(max) variance within an interdose interval is less than orequal to the Therapeutic Index of the active agent, and the in vivoabsorption of the active agent from the dosage form is enhanced uponadministration of the dosage form with food, however, the dosage form isstill safe even if taken in an un-prescribed manner, for example,without food. It is also an object of the present invention to providean abuse-resistant oral pharmaceutical dosage form that includes apharmacologically active agent and a controlled release carrier system,where the dosage form is suitable for use in a BID-dosing regimen, andfurther where the in vivo absorption of the active agent from the dosageform is enhanced upon administration of the dosage form with food. It isa related object of the invention to provide the above-described dosageforms where the in vivo pharmacological performance is characterized byhaving individual C_(min)/C_(max) variance at steady state that is lessthan or equal to about 2 to 3. It is also a related object of theinvention to provide the above-described dosage forms where thecontrolled release carrier system further provides a decreased risk ofmisuse or abuse, for example where such decreased risk of misuse orabuse is characterized by a low in vitro solvent extractability value ofthe active agent from the dosage form and/or by the absence of anysignificant effect on absorption of the active agent from the dosageform upon co-ingestion of the dosage form and alcohol by a subject. Ineach of the above-described related objects of the invention, thecontrolled release carrier system can be further characterized by aunique set of pharmaceutical excipients including solvents, carriermaterials, network formers and viscosity enhancing agents. In certainpreferred embodiments, the active agent can be an opioid,CNS-depressant, or CNS-stimulant that has a particularly high potentialfor abuse, diversion or other misuse. Preferably, the active agent cancomprise an opioid, an amphetamine, or a methylphenidate, in each caseeither as a salt or as a free base.

It is yet a further object of the present invention to provide anabuse-resistant oral pharmaceutical dosage form that includes an opioidanalgesic agent and a controlled release carrier system. The controlledrelease carrier system provides for controlled in vivo release of theagent characterized in that the individual steady state C_(min)/C_(max)variance within an interdose interval is less than or equal to theTherapeutic Index of the active agent, and the pharmacokinetic in vivorelease performance of the opioid analgesic agent from the controlledrelease carrier system is characterized by a T_(max) of at least about 4hours after ingestion by the subject. It is also an object of thepresent invention to provide an abuse-resistant oral pharmaceuticaldosage form that includes an opioid analgesic agent and a controlledrelease carrier system, where the dosage form is suitable for use in aBID-dosing regimen, and further wherein the pharmacokinetic in vivorelease performance of the opioid analgesic agent from the controlledrelease carrier system is characterized by a T_(max) of at least about 4hours after ingestion by the subject. It is a related object of theinvention to provide the above-described dosage forms wherein the invivo absorption of the opioid analgesic agent from the dosage form isenhanced upon administration of the dosage form with food, or,conversely, wherein in vivo release of the opioid analgesic agent fromthe controlled release carrier system is substantially free from foodeffect. It is a further related object of the invention to provide theabove-described dosage forms where the in vivo pharmacologicalperformance is characterized by having individual C_(min)/C_(max)variance at steady state is less than or equal to about 2 to 3. It isalso a related object of the invention to provide the above-describeddosage forms where the controlled release carrier system furtherprovides a decreased risk of misuse or abuse, for example where suchdecreased risk of misuse or abuse is characterized by a low in vitrosolvent extractability value of the opioid analgesic agent from thedosage form and/or by the absence of any significant effect onabsorption of the opioid analgesic agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject. In each of theabove-described related objects of the invention, the controlled releasecarrier system can be further characterized by a unique set ofpharmaceutical excipients including solvents, carrier materials, networkformers and viscosity enhancing agents.

It is a yet even further object of the present invention to provide anabuse-resistant oral pharmaceutical dosage form that includes apharmacologically active agent and a controlled release carrier system.The controlled release carrier system provides for controlled in vivorelease of the agent characterized in that the individual steady stateC_(min)/C_(max) variance within an interdose interval is less than orequal to the Therapeutic Index of the active agent, and the carriersystem includes a High Viscosity Liquid Carrier Material (“HVLCM”), anetwork former and at least one viscosity enhancing agent. It is also anobject of the present invention to provide an abuse-resistant oralpharmaceutical dosage form that includes a pharmacologically activeagent and a controlled release carrier system, where the dosage form issuitable for use in a BID-dosing regimen, and further where thecontrolled release carrier system includes a High Viscosity LiquidCarrier Material (“HVLCM”), a network former and at least one viscosityenhancing agent. It is a related object of the invention to provide theabove-described dosage forms wherein the in vivo absorption of theactive agent from the dosage form is enhanced upon administration of thedosage form with food, or, conversely, wherein in vivo release of theactive agent from the controlled release carrier system is substantiallyfree from food effect. It is a related object of the invention toprovide the above-described dosage forms where the in vivopharmacological performance is characterized by having individualC_(min)/C_(max) variance at steady state is less than or equal to about2 to 3. It is also a related object of the invention to provide theabove-described dosage forms where the controlled release carrier systemfurther provides a decreased risk of misuse or abuse, for example wheresuch decreased risk of misuse or abuse is characterized by a low invitro solvent extractability value of the active agent from the dosageform and/or by the absence of any significant effect on absorption ofthe active agent from the dosage form upon co-ingestion of the dosageform and alcohol by a subject. In each of the above-described relatedobjects of the invention, the controlled release carrier system can befurther characterized by a unique set of pharmaceutical excipientsincluding certain combinations of solvents, viscosity enhancing agents,and the like. In certain preferred embodiments, the active agent can bean opioid, CNS-depressant, or CNS-stimulant that has a particularly highpotential for abuse, diversion or other misuse. Preferably, the activeagent can comprise an opioid, an amphetamine, or a methylphenidate, ineach case either as a salt or as a free base.

It is also an object of the present invention to provide anabuse-resistant oral pharmaceutical dosage form that includes apharmacologically active agent and a controlled release carrier system.The controlled release carrier system provides for controlled in vivorelease of the agent characterized in that the individual steady stateC_(min)/C_(max) variance within an interdose interval is less than orequal to the Therapeutic Index of the active agent, more particularly,the individual C_(min)/C_(max) variance at steady state is less than orequal to about 2 to 3. It is also an object of the present invention toprovide an abuse-resistant oral pharmaceutical dosage form that includesa pharmacologically active agent and a controlled release carriersystem, where the dosage form is suitable for use in a BID-dosingregimen, and further where the pharmacokinetic in vivo releaseperformance of the active agent from the controlled release carriersystem is characterized by a T_(max) of at least about 4 hours afteringestion by the subject. It is a related object of the invention toprovide the above-described dosage forms wherein the in vivo absorptionof the active agent from the dosage form is enhanced upon administrationof the dosage form with food, or, conversely, wherein in vivo release ofthe active agent from the controlled release carrier system issubstantially free from food effect. It is a related object of theinvention to provide the above-described dosage forms where thecontrolled release carrier system further provides a decreased risk ofmisuse or abuse, for example where such decreased risk of misuse orabuse is characterized by a low in vitro solvent extractability value ofthe active agent from the dosage form and/or by the absence of anysignificant effect on absorption of the active agent from the dosageform upon co-ingestion of the dosage form and alcohol by a subject. Ineach of the above-described related objects of the invention, thecontrolled release carrier system can be further characterized by aunique set of pharmaceutical excipients including certain combinationsof solvents, viscosity enhancing agents, and the like. In certainpreferred embodiments, the active agent can be an opioid,CNS-depressant, or CNS-stimulant that has a particularly high potentialfor abuse, diversion or other misuse. Preferably, the active agent cancomprise an opioid, an amphetamine, or a methylphenidate, in each caseeither as a salt or as a free base.

It is a further object of the present invention to provide anabuse-resistant oral pharmaceutical dosage form that includes apharmacologically active agent and a controlled release carrier system.The controlled release carrier system includes a High Viscosity LiquidCarrier Material (“HVLCM”), a network former and at least one viscosityenhancing agent. It is also an object of the present invention toprovide the above-described dosage forms wherein the in vivo absorptionof the active agent from the dosage form is enhanced upon administrationof the dosage form with food, or, conversely, wherein in vivo release ofthe active agent from the controlled release carrier system issubstantially free from food effect. It is a related object of theinvention to provide the above-described dosage forms where thecontrolled release carrier system further provides a decreased risk ofmisuse or abuse, for example where such decreased risk of misuse orabuse is characterized by a low in vitro solvent extractability value ofthe active agent from the dosage form and/or by the absence of anysignificant effect on absorption of the active agent from the dosageform upon co-ingestion of the dosage form and alcohol by a subject. Ineach of the above-described related objects of the invention, thecontrolled release carrier system can be further characterized by aunique set of pharmaceutical excipients including certain combinationsof solvents, viscosity enhancing agents, and the like. In certainpreferred embodiments, the active agent can be an opioid,CNS-depressant, or CNS-stimulant that has a particularly high potentialfor abuse, diversion or other misuse. Preferably, the active agent cancomprise an opioid, an amphetamine, or a methylphenidate, in each caseeither as a salt or as a free base.

It is yet a further object of the invention to provide anabuse-resistant oral pharmaceutical dosage form including apharmacologically active agent and a controlled release carrier system,wherein the carrier system provides at least 8 hours of substantiallyconstant in vitro release of the active agent when tested in an USP TypeII Dissolution Apparatus with a stationary basket assembly using apaddle speed of 100 rpm and 0.1N HCl dissolution media containingsurfactant; and 20% or less of the active agent is extractable from thedosage form in an in vitro solvent extraction test using EtOH (100proof) as the extraction solvent, at ambient temperature (RT), for 1hour. It is a related object of the invention to provide anabuse-resistant oral pharmaceutical dosage form including apharmacologically active agent and a controlled release carrier system,wherein the carrier system provides at least 8 hours of substantiallyconstant in vitro release of the active agent when tested in an USP TypeII Dissolution Apparatus with a stationary basket assembly using apaddle speed of 100 rpm and 0.1N HCl dissolution media containingsurfactant; and 30% or less of the active agent is extractable from saiddosage form in an in vitro solvent extraction test using a panel ofextraction solvents at ambient temperature (RT), for 1 hour.

It is a further object of the invention to provide an oralpharmaceutical dosage form that includes a pharmacologically activeagent and a controlled release carrier system, where the controlledrelease carrier system includes an HVLCM, a network former, a rheologymodifier and a hydrophilic agent, and the dosage form isabuse-resistant. It is a related object of the invention to provide theabove-described dosage form wherein the controlled release carriersystem also includes one or more of the following additional components:a viscosity enhancing agent; a solvent; and a stabilizer agent. Inparticular embodiments, the HVLCM can comprise sucrose acetateisobutyrate (“SAM”), the network former can comprise cellulose acetatebutyrate (“CAB”), the rheology modifier can comprise isopropyl myristate(“IPM”), the hydrophilic agent can comprise hydroxyethyl cellulose(“HEC”) and therefore also serve as a viscosity enhancing agent, theviscosity enhancing agent can also be a silicon dioxide, the stabilizercan comprise butylhydroxyl toluene (“BHT”), and the active agent cancomprise an opioid, either as a salt or as a free base.

It is another object of the invention to provide a controlled releaseoral pharmaceutical dosage form that includes an opioid active agent,where the dosage form provides effective analgesia to a subject whendosed on a twice per day (BID) dosing schedule, and further where thedosage form has one or more of the following abuse-resistant performancefeatures (which may be assessed using the methodology of Example 4): (a)when exposed to extraction in 100 proof ethanol at room temperature for5 minutes, the dosage form releases less than about 5% of the opioid,preferably less than about 2% of the opioid; (b) when exposed toextraction in vinegar at room temperature for 5 minutes, the dosage formreleases less than about 5% of the opioid, preferably less than about 2%of the opioid; (c) when exposed to extraction in saturated baking sodasolution at room temperature for 5 minutes, the dosage form releasesless than about 5% of the opioid, preferably less than about 2% of theopioid; (d) when exposed to extraction in a cola soft drink at roomtemperature for 5 minutes, the dosage form releases less than about 10%of the opioid, preferably less than about 5% of the opioid; (e) whenexposed to extraction in 100 proof ethanol at room temperature for 60minutes, the dosage form releases less than about 20% of the opioid,preferably less than about 11% of the opioid; (f) when exposed toextraction in vinegar at room temperature for 60 minutes, the dosageform releases less than about 20% of the opioid, preferably less thanabout 12% of the opioid; (g) when exposed to extraction in saturatedbaking soda solution at room temperature for 60 minutes, the dosage formreleases less than about 20% of the opioid, preferably less than about12% of the opioid; (h) when exposed to extraction in a cola soft drinkat room temperature for 60 minutes, the dosage form releases less thanabout 30% of the opioid, preferably less than about 22% of the opioid;(i) when exposed to extraction in 100 proof ethanol at 60° C. for 5minutes, the dosage form releases less than about 15% of the opioid,preferably less than about 11% of the opioid; (j) when exposed toextraction in vinegar at 60° C. for 5 minutes, the dosage form releasesless than about 15% of the opioid, preferably less than about 11% of theopioid; (k) when exposed to extraction in saturated baking soda solutionat 60° C. for 5 minutes, the dosage form releases less than about 15% ofthe opioid, preferably less than about 11% of the opioid; (1) whenexposed to extraction in a cola soft drink at 60° C. for 5 minutes, thedosage form releases less than about 45% of the opioid, preferably lessthan about 30% of the opioid; (m) when exposed to extraction in 100proof ethanol at 60° C. for 60 minutes, the dosage form releases lessthan about 33% of the opioid, preferably less than about 26% of theopioid; (n) when exposed to extraction in vinegar at 60° C. for 60minutes, the dosage form releases less than about 33% of the opioid,preferably less than about 20% of the opioid; (o) when exposed toextraction in saturated baking soda solution at 60° C. for 60 minutes,the dosage form releases less than about 33% of the opioid, preferablyless than about 23% of the opioid; (p) when exposed to extraction in acola soft drink at 60° C. for 60 minutes, the dosage form releases lessthan about 60% of the opioid, preferably less than about 45% of theopioid; (q) when exposed to extraction in a panel of extraction solventsincluding vinegar, hot tea, saturated baking soda and a cola soft drink,each at 25° C. for 60 minutes, releases less than about 20% of theopioid, preferably less than about 15% of the opioid; (r) when exposedto extraction in a panel of aqueous buffer extraction solutions rangingfrom pH 1 to pH 12, each at 25° C. for 60 minutes, releases less thanabout 15% of the opioid, preferably less than about 12% of the opioid;(s) when physically disrupted by crushing the dosage form and exposed toextraction in a panel of aqueous extraction solutions including water at25° C., water at 60-70° C., 0.1N HCL at 25° C., and 100 proof ethanol at25° C., each for 60 minutes, releases less than about 40% of the opioid,preferably less than about 35% of the opioid; and/or (t) when physicallydisrupted by microwaving the dosage form and then exposed to extractionin a panel of aqueous extraction solutions including water, 0.1N HCL,and 100 proof ethanol, each at 25° C. for 60 minutes, releases less thanabout 25% of said opioid, preferably less than about 20% of the opioid.In particular embodiments, the opioid is oxycodone, oxymorphone,hydrocodone, or hydromorphone and can be present in either salt or freebase form. In one preferred embodiment, the opioid is oxycodone.

It is still a further object of the invention to provide safer methodsof treatment (including palliative care) to a patient in need of suchtreatment. The methods entail administration of the abuse-resistant oralpharmaceutical dosage forms of the present invention. More particularly,it is an object of the invention to provide a method for establishingand maintaining analgesia in a subject by repetitive administration ofan oral analgesic dosage form, wherein the dosage form isabuse-resistant therefore providing a safer method of treatment. Thedosage form that is used in the instant method includes a controlledrelease carrier system and an analgesic agent, and the controlledrelease carrier system provides for controlled in vivo release of theanalgesic agent characterized in that the individual steady stateC_(min)/C_(max) variance within an interdose interval is less than orequal to the Therapeutic Index of the analgesic agent. It is also anobject of the present invention to provide a method for establishing andmaintaining analgesia in a subject by repetitive administration of anoral analgesic dosage form, wherein the dosage form is abuse-resistantand is suitable for use in a BID-dosing regimen. It is a related objectof the invention to provide methods wherein the in vivo pharmacologicalperformance of the dosage forms is characterized by having individualC_(min)/C_(max) variance at steady state is less than or equal to about2 to 3. It is also a related object of the invention to provide theabove methods using dosage forms where the controlled release carriersystem further provides a decreased risk of misuse or abuse, for examplewhere such decreased risk of misuse or abuse is characterized by a lowin vitro solvent extractability value of the analgesic agent from thedosage form and/or by the absence of any significant effect onabsorption of the analgesic agent from the dosage form upon co-ingestionof the dosage form and alcohol by a subject. It is a still furtherrelated object of the invention to provide a method for establishing andmaintaining analgesia in a subject by repetitive administration of anabuse-resistant oral analgesic dosage form, where the bioavailability ofthe analgesic agent is enhanced (e.g., the in vivo absorption of theagent from the dosage form is increased) upon co-administration of thedosage form with food. In particular embodiments, the methods entailrepetitive administration of the above dosage forms where the analgesicagent is an opioid, and in a preferred embodiment, the opioid is presentin the dosage form in its free base form.

It is another object of the invention to provide a method forestablishing and maintaining analgesia in a subject by repetitiveadministration of an oral analgesic dosage form, wherein the dosage formincludes a controlled release carrier system and an analgesic agent, andthe controlled release carrier system includes an HVLCM, a networkformer and at least one viscosity enhancing agent. In a related objectof the invention, the dosage form is abuse-resistant, thereforeproviding a safer method of treatment. It is another related object toprovide a method for establishing and maintaining analgesia in a subjectby repetitive administration of an oral analgesic dosage form, whereinthe dosage form includes the above-described controlled release carriersystem that further provides for controlled in vivo release of theanalgesic agent characterized in that the individual steady stateC_(min)/C_(max) variance within an interdose interval is less than orequal to the Therapeutic Index of the analgesic agent. It is also anobject of the present invention to provide a method for establishing andmaintaining analgesia in a subject by repetitive administration of anoral analgesic dosage form, wherein the dosage form is suitable for usein a BID-dosing regimen. It is a related object of the invention toprovide methods wherein the in vivo pharmacological performance of thedosage forms is characterized by having individual C_(min)/C_(max)variance at steady state is less than or equal to about 2 to 3. It isalso a related object of the invention to provide the above methodsusing dosage forms where the controlled release carrier system furtherprovides a decreased risk of misuse or abuse, for example where suchdecreased risk of misuse or abuse is characterized by a low in vitrosolvent extractability value of the analgesic agent from the dosage formand/or by the absence of any significant effect on absorption of theanalgesic agent from the dosage form upon co-ingestion of the dosageform and alcohol by a subject. It is a still further related object ofthe invention to provide a method for establishing and maintaininganalgesia in a subject by repetitive administration of anabuse-resistant oral analgesic dosage form, where the bioavailability ofthe analgesic agent is enhanced (e.g., the in vivo absorption of theagent from the dosage form is increased) upon co-administration of thedosage form with food. In particular embodiments, the methods entailrepetitive administration of the above dosage forms where the analgesicagent is an opioid, and in a preferred embodiment, the opioid is presentin the dosage form in its free base form.

It is an advantage of the present invention that the abuse-resistantoral dosage forms are able to provide enhanced safety features and/orabuse-resistance properties in addition to enhanced in vivopharmacological performance as compared with prior dosage forms. It is afurther advantage of the invention that the inventive dosage forms canbe readily constructed and used to provide a wide range of safer andmore efficacious pharmacological solutions to the medical field.

These and other objects, aspects and advantages of the present inventionwill readily occur to the skilled person upon reading the instantdisclosure and specification.

Points of the Invention

1. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent and a controlled release carrier system which comprises:

-   -   a high viscosity liquid carrier material (HVLCM);    -   a network former;    -   a rheology modifier;    -   a hydrophilic agent; and    -   a solvent.

2. The dosage form of point 1, wherein the pharmacologically activeagent is an opioid, a central nervous system (CNS) depressant or a CNSstimulant.

3. The dosage form of point 2, wherein the pharmacologically activeagent is selected from oxycodone, oxymorphone, hydrocodone,hydromorphone, either in the free base form or a pharmaceuticallyacceptable salt form thereof.

4. The dosage form of point 2, wherein the pharmacologically activeagent is selected from amphetamine, methylphenidate, andpharmaceutically acceptable salts thereof.

5. The dosage form of any one of the preceding points, wherein:

the HVLCM is sucrose acetate isobutyrate (SAIB);

the network former is selected from cellulose acetate butyrate (CAB),cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethylcellulose and cellulose triacetate;

the rheology modifier is selected from isopropyl myristate (IPM),caprylic/capric triglyceride, ethyl oleate, triethyl citrate, dimethylphthalate and benzyl benzoate;

the hydrophilic agent is selected from hydroxyethylcellulose (HEC),hydroxypropylcellulose, caboxymethylcellulose, polyethylene glycol andpolyvinylpyrrolidone; and

the solvent is selected from triacetin, N-methyl-2-pyrrolidone,2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate andglycofurol.

6. The dosage form of point 5, wherein (a) the HVLCM is SAIB, (b) thenetwork former is CAB, (c) the rheology modifier is IPM, (d) thehydrophilic agent is HEC, and (e) the solvent is triacetin.

7. The dosage form of any one of the preceding points, which comprises(a) from 1.3 to 35 wt % of the pharmacologically active agent, (b) from2 to 10 wt % of the network former, (c) from 0.1 to 20 wt % of therheology modifier, (d) from 1 to 8 wt % of the hydrophilic agent, (e)from 10 to 40 wt % of the solvent, and (f) from 30 to 60 wt % of theHVLCM.

8. The dosage form of any one of the preceding points, wherein thecontrolled release carrier system further comprises a viscosityenhancing agent.

9. The dosage form of point 8, wherein the viscosity enhancing agent isa silicon dioxide.

10. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent and a controlled release carrier system which comprises:

-   -   a HVLCM;    -   a network former;    -   a first viscosity enhancing agent;    -   a hydrophilic solvent; and    -   a hydrophobic solvent.

11. The dosage form of point 10, wherein the pharmacologically activeagent is an opioid, a central nervous system (CNS) depressant or a CNSstimulant.

12. The dosage form of point 11, wherein the pharmacologically activeagent is selected from oxycodone, oxymorphone, hydrocodone,hydromorphone, either in the free base form or a pharmaceuticallyacceptable salt form thereof.

13. The dosage form of point 11, wherein the pharmacologically activeagent is selected from amphetamine, methylphenidate, andpharmaceutically acceptable salts thereof

14. The dosage form of any one of points 10 to 13, wherein:

the HVLCM is SAM;

the network former is selected from CAB, cellulose acetate phthalate,ethyl cellulose, hydroxypropylmethyl cellulose and cellulose triacetate;

the first viscosity enhancing agent is HEC, hydroxypropylcellulose,carboxymethylcellulose, polyethylene glycol and polyvinylpyrrolidone;

the hydrophilic solvent is selected from triacetin,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,propylene carbonate and glycofurol; and

the hydrophobic solvent is IPM.

15. The dosage form of point 14, wherein (a) the HVLCM is SAM, (b) thenetwork former is CAB, (c) the first viscosity enhancing agent is HEC,(d) the hydrophilic solvent is triacetin, and (e) the hydrophobicsolvent is IPM.

16. The dosage form of any one of the points 10 to 15, which comprises(a) from 1.3 to 35 wt % of the pharmacologically active agent, (b) from2 to 10 wt % of the network former, (c) from 1 to 8 wt % of the firstviscosity enhancing agent, (d) from 10 to 40 wt % of the hydrophilicsolvent, (e) from 0.1 to 20 wt % of the hydrophobic solvent, and (f)from 30 to 60 wt % of the HVLCM.

17. The dosage form of any one of points 10 to 16, which furthercomprises a second viscosity enhancing agent.

18. The dosage form of point 17, wherein the second viscosity enhancingagent is silicone dioxide.

19. The dosage form of any one of the preceding points furthercomprising a stabilizer agent.

20. The dosage form of point 19, wherein the stabilizer agent isbutylhydroxyl toluene (BHT).

21. The dosage form of any one of the preceding points, which providesat least 8 hours of substantially constant in vitro release of theactive agent when tested in an USP Type II Dissolution Apparatus with astainless steel stationary basket assembly using a paddle speed of 100rpm and 0.1N HCl dissolution media containing 0.5% sodium laurylsulfate; and 20% or less of said active agent is extracted from saiddosage form after 1 hour of extraction in 100 proof ethanol (EtOH) atambient temperature.

22. The dosage form of any one of the preceding points, wherein lessthan 20% of the active agent is extracted after 60 minutes of extractionin 100 proof EtOH at ambient temperature and less than 30% is extractedafter 60 minutes of extraction in 100 proof EtOH at 60° C.

23. The dosage form of any one of the preceding points, wherein theformulation of the active agent and the carrier system is encapsulatedwithin a capsule.

24. The dosage form of point 23, wherein the capsule comprises gelatin,hydroxyethylcellulose or hydroxypropylmethylcellulose.

25. The dosage form of point 23 or 24, wherein the capsule is packagedin unit dose blisters or multidose plastic bottles.

26. A process for the preparation of an oral pharmaceutical dosage formas defined in point 1, which process comprises:

(i) preheating the HVLCM;

(ii) mixing the solvent with the preheated HVLCM, thereby forming auniform solution of the HVLCM in the solvent;

(iii) dispersing the network former in the solution, thereby dissolvingthe network former in the solution;

(iv) mixing from 5 to 30% of the rheology modifier or, optionally, asolution of a stabilising agent and from 5 to 30% of the rheologymodifier with the formulation obtained in step (iii);

(v) mixing the pharmacologically active agent with the formulationobtained in step (iv);

(vi) mixing the hydrophilic agent with the formulation obtained in step(v);

(vii) optionally, mixing a viscosity enhancing agent with theformulation obtained in step (vi);

(viii) mixing the balance of the rheology modifier with the formulationobtained in step (vi) or, if step (vii) is effected, step (vii);

(ix) optionally, filling capsules with the formulation obtained in step(viii); and

(x) optionally, packaging the filled capsules into unit dose blisters ormultidose plastic bottles.

27. A process for the preparation of an oral pharmaceutical dosage formas defined in point 1, which process comprises:

(i) preheating the HVLCM;

(ii) mixing the solvent with the preheated HVLCM, thereby forming auniform solution of the HVLCM in the solvent;

(iii) optionally, mixing a solution of a stabilising agent and from 5 to30% of the rheology modifier with the solution obtained in step (ii);

(iv) mixing the rheology modifier or, if step (iii) is effected, thebalance of the rheology modifier with the solution obtained in step (ii)or (iii);

(v) optionally, mixing a viscosity enhancing agent with the formulationobtained in step (iv);

(vi) dispersing the network former in the solution obtained in step (iv)or, if step (v) is effected, step (v), thereby dissolving the networkformer in the solution;

(vii) mixing the pharmacologically active agent with the formulationobtained in step (vi);

(viii) mixing the hydrophilic agent with the formulation obtained instep (vii);

(ix) optionally, filling capsules with the formulation obtained in step(viii); and

(x) optionally, packaging the filled capsules into unit dose blisters ormultidose plastic bottles.

28. A process for the preparation of an oral pharmaceutical dosage formas defined in point 10, which process comprises:

(i) preheating the HVLCM;

(ii) mixing the hydrophilic solvent with the preheated HVLCM, therebyforming a uniform solution of the HVLCM in the solvent;

(iii) dispersing the network former in the solution, thereby dissolvingthe network former in the solution;

(iv) mixing from 5 to 30% of the hydrophobic solvent or, optionally, asolution of a stabilising agent and from 5 to 30% of the hydrophobicsolvent with the formulation obtained in step (iii);

(v) mixing the pharmacologically active agent with the formulationobtained in step (iv);

(vi) mixing the first viscosity enhancing agent with the formulationobtained in step (v);

(vii) optionally, mixing a second viscosity enhancing agent with theformulation obtained in step (vi);

(viii) mixing the balance of the hydrophobic solvent with theformulation obtained in step (vi) or, if step (vii) is effected, step(vii);

(ix) optionally, filling capsules with the formulation obtained in step(viii); and

(x) optionally, packaging the filled capsules into unit dose blisters ormultidose plastic bottles.

29. A process for the preparation of an oral pharmaceutical dosage formas defined in point 10, which process comprises:

(i) preheating the HVLCM;

(ii) mixing the hydrophilic solvent with the preheated HVLCM, therebyforming a uniform solution of the HVLCM in the solvent;

(iii) optionally, mixing a solution of a stabilising agent and from 5 to30% of the hydrophobic solvent with the solution obtained in step (ii);

(iv) mixing the hydrophobic solvent or, if step (iii) is effected, thebalance of the hydrophobic solvent with the solution obtained in step(ii) or (iii);

(v) optionally, mixing a second viscosity enhancing agent with theformulation obtained in step (iv);

(vi) dispersing the network former in the solution obtained in step (iv)or, if step (v) is effected, step (v), thereby dissolving the networkformer in the solution;

(vii) mixing the pharmacologically active agent with the formulationobtained in step (vi);

(viii) mixing the first viscosity enhancing agent with the formulationobtained in step (vii);

(ix) optionally, filling capsules with the formulation obtained in step(viii); and

(x) optionally, packaging the filled capsules into unit dose blisters ormultidose plastic bottles.

30. An oral pharmaceutical dosage form obtainable by a process asdefined in any one points 26 to 29.

31. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent and a controlled release carrier system, wherein:

-   -   said pharmaceutical dosage form is abuse-resistant; and    -   said controlled release carrier system provides for controlled        in vivo release of the agent characterized in that the        individual steady state C_(min)/C_(max) variance within an        interdose interval is less than or equal to the Therapeutic        Index of said active agent.

32. The dosage form of point 31, wherein the active agent is suspendedwithin the controlled release carrier system.

33. The dosage form of point 31, wherein the individual C_(min)/C_(max)variance at steady state is less than or equal to about 2 to 3.

34. The dosage form of point 31 suitable for use in a BID-dosingregimen.

35. The dosage form of point 31, wherein the active agent is an opioid.

36. The dosage form of point 31, wherein the active agent is in saltform.

37. The dosage form of point 31, wherein the controlled release carriersystem comprises an HVLCM and a network former.

38. The dosage form of point 37, wherein the controlled release carriersystem further comprises a plurality of hydrophilic excipients.

39. The dosage form of point 37, wherein the controlled release carriersystem further comprises a plurality of viscosity enhancing agents.

40. The dosage form of point 37, wherein the controlled release carriersystem further comprises a plurality of solvents.

41. The dosage form of point 40, wherein the solvents comprise ahydrophobic solvent and a hydrophilic solvent.

42. The dosage form of point 31, wherein the controlled release carriersystem further provides a decreased risk of misuse or abuse.

43. The dosage form of point 42, wherein said decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the active agent from the dosage form.

44. The dosage form of point 42, wherein said decreased risk of misuseor abuse is characterized by the absence of any significant effect onabsorption of the active agent from the dosage form upon co-ingestion ofthe dosage form and alcohol by a subject.

45. The dosage form of point 43, wherein said decreased risk of misuseor abuse is further characterized by the absence of any significanteffect on absorption of the active agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

46. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent and a controlled release carrier system, wherein:

-   -   said pharmaceutical dosage form is abuse-resistant;    -   said controlled release carrier system provides for controlled        in vivo release of the agent characterized in that the        individual steady state C_(min)/C_(max) variance within an        interdose interval is less than or equal to the Therapeutic        Index of said active agent; and    -   the in vivo absorption of said active agent from the dosage form        is enhanced upon administration of the dosage form with food.

47. The dosage form of point 46, wherein the active agent is suspendedwithin the controlled release carrier system.

48. The dosage form of point 46, wherein the individual C_(min)/C_(max)variance at steady state is less than or equal to about 2 to 3.

49. The dosage form of point 46 suitable for use in a BID-dosingregimen.

50. The dosage form of point 46, wherein the active agent is an opioid.

51. The dosage form of point 46, wherein the active agent is in the formof a free base.

52. The dosage form of point 46, wherein the controlled release carriersystem comprises an HVLCM and a network former.

53. The dosage form of point 52, wherein the controlled release carriersystem further comprises a plurality of hydrophilic excipients.

54. The dosage form of point 52, wherein the controlled release carriersystem further comprises a plurality of viscosity enhancing agents.

55. The dosage form of point 52, wherein the controlled release carriersystem further comprises a plurality of solvents.

56. The dosage form of point 55, wherein the solvents comprise ahydrophobic solvent and a hydrophilic solvent.

57. The dosage form of point 46, wherein the controlled release carriersystem further provides a decreased risk of misuse or abuse.

58. The dosage form of point 57, wherein said decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the active agent from the dosage form.

59. The dosage form of point 57, wherein said decreased risk of misuseor abuse is characterized by the absence of any significant effect onabsorption of the active agent from the dosage form upon co-ingestion ofthe dosage form and alcohol by a subject.

60. The dosage form of point 59, wherein said decreased risk of misuseor abuse is further characterized by the absence of any significanteffect on absorption of the active agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

61. A method of increasing the oral bioavailability of an active agentto a subject receiving therapy with the active agent, said methodcomprising orally administering to the subject the dosage form of point46 with food.

62. A method of increasing the extent of absorption of an active agentfrom an oral dosage form, said method comprising orally administering tothe subject the dosage form of point 46 with food.

63. An oral pharmaceutical dosage form comprising an opioid analgesicagent and a controlled release carrier system, wherein:

-   -   said pharmaceutical dosage form is abuse-resistant;    -   said controlled release carrier system provides for controlled        in vivo release of the agent characterized in that the        individual steady state C_(min)/C_(max) variance within an        interdose interval is less than or equal to the Therapeutic        Index of said active agent; and    -   the pharmacokinetic in vivo release performance of said opioid        analgesic agent from the controlled release carrier system is        characterized by a T_(max) of at least about 4 hours after        ingestion by the subject.

64. The dosage form of point 63, wherein the opioid analgesic agent issuspended within the carrier system.

65. The dosage form of point 63, wherein the individual C_(min)/C_(max)variance at steady state is less than or equal to about 2 to 3.

66. The dosage form of point 63 suitable for use in a BID dosingregimen.

67. The dosage form of point 63, wherein the opioid analgesic agent isin salt form.

68. The dosage form of point 63, wherein the opioid analgesic agent isin the form of a free base.

69. The dosage form of point 63, wherein the controlled release carriersystem comprises HVLCM and network former.

70. The dosage form of point 69, wherein the controlled release carriersystem further comprises a plurality of hydrophilic excipients.

71. The dosage form of point 69, wherein the controlled release carriersystem further comprises a plurality of viscosity enhancing agents.

72. The dosage form of point 69, wherein the controlled release carriersystem further comprises a plurality of solvents.

73. The dosage form of point 72, wherein the solvents comprise ahydrophobic solvent and a hydrophilic solvent.

74. The dosage form of point 63, wherein the in vivo release of saidopioid analgesic agent from the controlled release carrier system issubstantially free from food effect.

75. The dosage form of point 63, wherein the controlled release carriersystem further provides enhanced in vivo absorption of said opioidanalgesic agent from the dosage form upon administration of the dosageform with food.

76. The dosage form of point 63, wherein the controlled release carriersystem further provides a decreased risk of misuse or abuse.

77. The dosage form of point 76, wherein said decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the opioid analgesic agent from the dosage form.

78. The dosage form of point 76, wherein said decreased risk of misuseor abuse is characterized by the absence of any significant effect onabsorption of the opioid analgesic agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

79. The dosage form of point 78, wherein said decreased risk of misuseor abuse is further characterized by the absence of any significanteffect on absorption of the opioid analgesic agent from the dosage formupon co-ingestion of the dosage form and alcohol by a subject.

80. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent and a controlled release carrier system, wherein:

-   -   said oral pharmaceutical dosage form is abuse-resistant;    -   said controlled release carrier system provides for controlled        in vivo release of the agent characterized in that the        individual steady state C_(min)/C_(max) variance within an        interdose interval is less than or equal to the Therapeutic        Index of said active agent; and    -   said controlled release carrier system comprises an HVLCM, a        network former, and at least one viscosity enhancing agent.

81. The dosage form of point 80, wherein the active agent is suspendedwithin the controlled release carrier system.

82. The dosage form of point 80, wherein the individual C_(min)/C_(max)variance at steady state is less than or equal to about 2 to 3.

83. The dosage form of point 80 suitable for use in a BID dosingregimen.

84. The dosage form of point 80, wherein the active agent is an opioid.

85. The dosage form of point 80, wherein the active agent is in saltform.

86. The dosage form of point 80, wherein the active agent is in the formof a free base.

87. The dosage form of point 80, wherein the controlled release carriersystem further comprises a surfactant.

88. The dosage form of point 80, wherein the controlled release carriersystem comprises a plurality of hydrophilic excipients.

89. The dosage form of point 80, wherein the controlled release carriersystem further comprises a second viscosity enhancing agent.

90. The dosage form of point 80, wherein the controlled release carriersystem comprises a plurality of solvents.

91. The dosage form of point 90, wherein the solvents comprise ahydrophobic solvent and a hydrophilic solvent.

92. The dosage form of point 80, wherein the in vivo release of saidactive agent from the controlled release carrier system is substantiallyfree from food effect.

93. The dosage form of point 80, wherein the controlled release carriersystem further provides enhanced in vivo absorption of said active agentfrom the dosage form upon administration of the dosage form with food.

94. The dosage form of point 80, wherein the controlled release carriersystem further provides a decreased risk of misuse or abuse.

95. The dosage form of point 94, wherein said decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the active agent from the dosage form.

96. The dosage form of point 94, wherein said decreased risk of misuseor abuse is characterized by the absence of any significant effect onabsorption of the active agent from the dosage form upon co-ingestion ofthe dosage form and alcohol by a subject.

97. The dosage form of point 96, wherein said decreased risk of misuseor abuse is further characterized by the absence of any significanteffect on absorption of the active agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

98. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent and a controlled release carrier system, wherein:

-   -   said oral pharmaceutical dosage form is abuse-resistant;    -   said controlled release carrier system provides for controlled        in vivo release of the agent characterized in that the        individual steady state C_(min)/C_(max) variance within an        interdose interval is less than or equal to the Therapeutic        Index of said active agent; and    -   said individual C_(min)/C_(max) variance at steady state is less        than or equal to about 2 to 3.

99. The dosage form of point 98 suitable for use in a BID dosingregimen.

100. The dosage form of point 98, wherein the pharmacokinetic in vivorelease performance of said active agent from the controlled releasecarrier system is characterized by a T_(max) of at least about 4 hoursafter ingestion by the subject.

101. The dosage form of point 98, wherein said controlled releasecarrier system comprises an HVLCM, a network former, and at least oneviscosity enhancing agent.

102. The dosage form of point 98, wherein the active agent is an opioid.

103. The dosage form of point 98, wherein the active agent is in saltform.

104. The dosage form of point 98, wherein the active agent is in theform of a free base.

105. The dosage form of point 101, wherein the controlled releasecarrier system further comprises a surfactant.

106. The dosage form of point 101, wherein the controlled releasecarrier system further comprises a plurality of hydrophilic excipients.

107. The dosage form of point 101, wherein the controlled releasecarrier system further comprises a second viscosity enhancing agent.

108. The dosage form of point 101, wherein the controlled releasecarrier system further comprises a plurality of solvents.

109. The dosage form of point 108, wherein the solvents comprise ahydrophobic solvent and a hydrophilic solvent.

110. The dosage form of point 98, wherein the in vivo release of saidactive agent from the controlled release carrier system is substantiallyfree from food effect.

111. The dosage form of point 98, wherein the controlled release carriersystem further provides enhanced in vivo absorption of said active agentfrom the dosage form upon administration of the dosage form with food.

112. The dosage form of point 98, wherein the controlled release carriersystem further provides a decreased risk of misuse or abuse.

113. The dosage form of point 112, wherein said decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the active agent from the dosage form.

114. The dosage form of point 112, wherein said decreased risk of misuseor abuse is characterized by the absence of any significant effect onabsorption of the active agent from the dosage form upon co-ingestion ofthe dosage form and alcohol by a subject.

115. The dosage form of point 114, wherein said decreased risk of misuseor abuse is further characterized by the absence of any significanteffect on absorption of the active agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

116. An abuse-resistant oral pharmaceutical dosage form comprising apharmacologically active agent and a controlled release carrier system,wherein:

-   -   said controlled release carrier system comprises an HVLCM, a        network former, and at least one viscosity enhancing agent.

117. The dosage form of point 116, wherein the viscosity enhancing agentis a synthetic polymer.

118. The dosage form of point 117, wherein the synthetic polymer is acellulose derivative.

119. The dosage form of point 116, wherein the active agent is anopioid.

120. The dosage form of point 116, wherein the active agent is in saltform.

121. The dosage form of point 116, wherein the active agent is in theform of a free base.

122. The dosage form of point 116, wherein the controlled releasecarrier system further comprises a surfactant.

123. The dosage form of point 116, wherein the controlled releasecarrier system further comprises a plurality of hydrophilic excipients.

124. The dosage form of point 116, wherein the controlled releasecarrier system further comprises a second viscosity enhancing agent.

125. The dosage form of point 124, wherein the second viscosityenhancing agent comprises a stiffening agent.

126. The dosage form of point 125, wherein the second viscosityenhancing agent comprises a SiO₂.

127. The dosage form of point 116, wherein the controlled releasecarrier system further comprises a plurality of solvents.

128. The dosage form of point 127, wherein the solvents comprise ahydrophobic solvent and a hydrophilic solvent.

129. The dosage form of point 116, wherein the in vivo release of saidactive agent from the controlled release carrier system is substantiallyfree from food effect.

130. The dosage form of point 116, wherein the controlled releasecarrier system further provides enhanced in vivo absorption of saidactive agent from the dosage form upon administration of the dosage formwith food.

131. The dosage form of point 116, wherein the controlled releasecarrier system further provides a decreased risk of misuse or abuse.

132. The dosage form of point 131, wherein said decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the active agent from the dosage form.

133. The dosage form of point 131, wherein said decreased risk of misuseor abuse is characterized by the absence of any significant effect onabsorption of the active agent from the dosage form upon co-ingestion ofthe dosage form and alcohol by a subject.

134. The dosage form of point 133, wherein said decreased risk of misuseor abuse is further characterized by the absence of any significanteffect on absorption of the active agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

135. An abuse-resistant oral pharmaceutical dosage form comprising apharmacologically active agent and a controlled release carrier system,wherein:

-   -   said controlled release carrier system provides at least 8 hours        of substantially constant in vitro release of the active agent        when tested in an USP Type II Dissolution Apparatus with a        stationary basket assembly using a paddle speed of 100 rpm and        0.1N HCl dissolution media containing surfactant; and    -   20% or less of said active agent is extractable from said dosage        form in an in vitro solvent extraction test using EtOH (100        proof) as the extraction solvent, at RT, for 1 hour.

136. An abuse-resistant oral pharmaceutical dosage form comprising apharmacologically active agent and a controlled release carrier system,wherein:

-   -   said controlled release carrier system provides at least 8 hours        of substantially constant in vitro release of the active agent        when tested in an USP Type II Dissolution Apparatus with a        stationary basket assembly using a paddle speed of 100 rpm and        0.1N HCl dissolution media containing surfactant; and

30% or less of said active agent is extractable from said dosage form inan in vitro solvent extraction test using a panel of extraction solventsat RT, for 1 hour.

137. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent and a controlled release carrier system, wherein:

-   -   said controlled release carrier system comprises an HVLCM, a        network former, a rheology modifier and a hydrophilic agent; and    -   said dosage form is abuse-resistant.

138. The dosage form of point 137, wherein the controlled releasecarrier system further comprises a viscosity enhancing agent.

139. The dosage form of point 138, wherein the hydrophilic agent alsoserves as a second viscosity enhancing agent.

140. The dosage form of any one of points 137 to 139, wherein thehydrophilic agent is hydroxyethyl cellulose (HEC).

141. The dosage form of any one of points 137 to 140, wherein the HVLCMis sucrose acetate isobutyrate (SAM).

142. The dosage form of any one of points 137 to 141 further comprisinga solvent.

143. The dosage form of point 142, wherein the solvent is triacetin.

144. The dosage form of point 138, wherein the viscosity enhancing agentis a silicon dioxide.

145. The dosage form of any one of points 137 to 144, wherein thenetwork former is cellulose acetate butyrate (CAB).

146. The dosage form of any one of points 137 to 145, wherein therheology modifier is isopropyl myristate (IPM).

147. The dosage form of any one of points 137 to 146, wherein the activeagent is an opioid.

148. The dosage form of point 147, wherein the opioid is oxycodone,oxymorphone, hydrocodone, or hydromorphone.

149. The dosage form of point 148, wherein the opioid is oxycodone.

150. The dosage form of any one of points 147-149, wherein the opioid ispresent in the form of a free base.

151. The dosage form of any one of points 147-149, wherein the opioid ispresent in the form of a salt.

152. The dosage form of any one of points 137 to 151 further comprisinga stabilizer agent.

153. The dosage form of point 152, wherein the stabilizer agent isbutylhydroxyl toluene (BHT).

154. The dosage form of any one of points 137 to 153, wherein the activeagent is micronized.

155. A method for establishing and maintaining analgesia in a subject byrepetitive administration of an oral analgesic dosage form, wherein:

-   -   said dosage form is abuse-resistant;    -   said dosage form comprises a controlled release carrier system        and an analgesic agent; and    -   said controlled release carrier system provides for controlled        in vivo release of the analgesic agent characterized in that the        individual steady state C_(min)/C_(max) variance within an        interdose interval is less than or equal to the Therapeutic        Index of said analgesic agent.

156. The method of point 155, wherein the individual C_(min)/C_(max)variance at steady state is less than or equal to about 2 to 3.

157. The method of point 155, wherein said repetitive administrationcomprises a BID-dosing regimen.

158. The method of point 155, wherein the controlled release carriersystem further provides a decreased risk of misuse or abuse.

159. The method of point 158, wherein said decreased risk of misuse orabuse is characterized by a low in vitro solvent extractability value ofthe analgesic agent from the dosage form.

160. The method of point 158, wherein said decreased risk of misuse orabuse is characterized by the absence of any significant effect onabsorption of the analgesic agent from the dosage form upon co-ingestionof the dosage form and alcohol by a subject.

161. The method of point 159, wherein said decreased risk of misuse orabuse is further characterized by the absence of any significant effecton absorption of the analgesic agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

162. The method of point 155, wherein the in vivo absorption of saidanalgesic agent from the dosage form is enhanced upon administration ofthe dosage form with food.

163. The method of point 155, wherein the analgesic agent comprises anopioid.

164. The method of point 163, wherein the opioid is present in thedosage form as a free base.

165. A method for establishing and maintaining analgesia in a subject byrepetitive administration of an oral analgesic dosage form, wherein:

-   -   said dosage form comprises a controlled release carrier system        and an analgesic agent, and further wherein said controlled        release carrier system comprises an HVLCM, a network former, and        at least one viscosity enhancing agent.

166. The method of point 165, wherein the dosage form isabuse-resistant.

167. The method of point 165, wherein said controlled release carriersystem provides for controlled in vivo release of the analgesic agentcharacterized in that the individual steady state C_(min)/C_(max)variance within an interdose interval is less than or equal to theTherapeutic Index of said analgesic agent.

168. The method of point 167, wherein the individual C_(min)/C_(max)variance at steady state is less than or equal to about 2 to 3.

169. The method of point 165, wherein said repetitive administrationcomprises a BID-dosing regimen.

170. The method of point 165, wherein the controlled release carriersystem further provides a decreased risk of misuse or abuse.

171. The method of point 170, wherein said decreased risk of misuse orabuse is characterized by a low in vitro solvent extractability value ofthe analgesic agent from the dosage form.

172. The method of point 170, wherein said decreased risk of misuse orabuse is characterized by the absence of any significant effect onabsorption of the analgesic agent from the dosage form upon co-ingestionof the dosage form and alcohol by a subject.

173. The method of point 171, wherein said decreased risk of misuse orabuse is further characterized by the absence of any significant effecton absorption of the analgesic agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

174. The method of point 165, wherein the in vivo absorption of saidanalgesic agent from the dosage form is enhanced upon administration ofthe dosage form with food.

175. The method of point 165, wherein the analgesic agent comprises anopioid.

176. The method of point 175, wherein the opioid is present in thedosage form as a free base.

177. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in 100 proof ethanol at room temperature for 5 minutesreleases less than about 2% of said opioid.

178. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in vinegar at room temperature for 5 minutes releases lessthan about 2% of said opioid.

179. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a saturated baking soda solution at room temperature for 5minutes releases less than about 2% of said opioid.

180. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a cola soft drink at room temperature for 5 minutesreleases less than about 5% of said opioid.

181. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in 100 proof ethanol at room temperature for 60 minutesreleases less than about 11% of said opioid.

182. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in vinegar at room temperature for 60 minutes releases lessthan about 12% of said opioid.

183. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a saturated baking soda solution at room temperature for60 minutes releases less than about 12% of said opioid.

184. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a cola soft drink at room temperature for 60 minutesreleases less than about 22% of said opioid.

185. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in 100 proof ethanol at room temperature for 5 minutesreleases less than about 5% of said opioid.

186. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in vinegar at room temperature for 5 minutes releases lessthan about 5% of said opioid.

187. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a saturated baking soda solution at room temperature for 5minutes releases less than about 5% of said opioid.

188. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a cola soft drink at room temperature for 5 minutesreleases less than about 10% of said opioid.

189. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in 100 proof ethanol at room temperature for 60 minutesreleases less than about 20% of said opioid.

190. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in vinegar at room temperature for 60 minutes releases lessthan about 20% of said opioid.

191. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a saturated baking soda solution at room temperature for60 minutes releases less than about 20% of said opioid.

192. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a cola soft drink at room temperature for 60 minutesreleases less than about 30% of said opioid.

193. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in 100 proof ethanol at 60° C. for 5 minutes releases lessthan about 11% of said opioid.

194. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in vinegar at 60° C. for 5 minutes releases less than about11% of said opioid.

195. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a saturated baking soda solution at 60° C. for 5 minutesreleases less than about 11% of said opioid.

196. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a cola soft drink at 60° C. for 5 minutes releases lessthan about 30% of said opioid.

197. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in 100 proof ethanol at 60° C. for 60 minutes releases lessthan about 26% of said opioid.

198. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in vinegar at 60° C. for 60 minutes releases less than about20% of said opioid.

199. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a saturated baking soda solution at 60° C. for 60 minutesreleases less than about 23% of said opioid.

200. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a cola soft drink at 60° C. for 60 minutes releases lessthan about 45% of said opioid.

201. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in 100 proof ethanol at 60° C. for 5 minutes releases lessthan about 15% of said opioid.

202. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in vinegar at 60° C. for 5 minutes releases less than about15% of said opioid.

203. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a saturated baking soda solution at 60° C. for 5 minutesreleases less than about 15% of said opioid.

204. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a cola soft drink at 60° C. for 5 minutes releases lessthan about 45% of said opioid.

205. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in 100 proof ethanol at 60° C. for 60 minutes releases lessthan about 33% of said opioid.

206. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in vinegar at 60° C. for 60 minutes releases less than about33% of said opioid.

207. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a saturated baking soda solution at 60° C. for 60 minutesreleases less than about 33% of said opioid.

208. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a cola soft drink at 60° C. for 60 minutes releases lessthan about 60% of said opioid.

209. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a panel of extraction solvents including vinegar, hot tea,saturated baking soda and a cola soft drink, each at 25° C. for 60minutes, releases less than about 20% of said opioid.

210. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when exposed toextraction in a panel of aqueous buffer extraction solutions rangingfrom pH 1 to pH 12, each at 25° C. for 60 minutes, releases less thanabout 15% of said opioid.

211. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when physically disruptedby crushing said dosage form and exposed to extraction in a panel ofaqueous extraction solutions including water at 25° C., water at 60-70°C., 0.1N HCL at 25° C., and 100 proof ethanol at 25° C., each for 60minutes, releases less than about 40% of said opioid.

212. A controlled release oral pharmaceutical dosage form comprising anopioid active agent, wherein said dosage form provides effectiveanalgesia to a subject when dosed on a twice per day (BID) dosingschedule and further wherein said dosage form, when physically disruptedby microwaving said dosage form and then exposed to extraction in apanel of aqueous extraction solutions including water, 0.1N HCL, and 100proof ethanol, each at 25° C. for 60 minutes, releases less than about25% of said opioid.

213. The dosage form of any one of points 177 to 212, wherein the opioidis oxycodone, oxymorphone, hydrocodone, or hydromorphone.

214. The dosage form of point 213, wherein the opioid is oxycodone.

215. The dosage form of any one of points 177-214, wherein the opioid ispresent in the form of a free base.

216. The dosage form of any one of points 177-214, wherein the opioid ispresent in the form of a salt.

217. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent and a controlled release carrier system, wherein:

-   -   said pharmaceutical dosage form is abuse-resistant; and    -   said dosage form is suitable for twice per day (BID) dosing.

218. An oral pharmaceutical dosage form comprising an opioid activeagent and a controlled release carrier system, wherein saidpharmaceutical dosage form is abuse-resistant and formulated for BIDadministration.

219. An oral pharmaceutical dosage form comprising an opioid activeagent and a controlled release carrier system, wherein saidpharmaceutical dosage form is abuse-resistant and provides effectivepain relief for at least 12 hours.

220. The dosage form of any one of points 217 to 219, wherein the activeagent is oxycodone, oxymorphone, hydrocodone, or hydromorphone.

221. The dosage form of point 220, wherein the opioid is oxycodone.

222. The dosage form of any one of points 217 to 221, wherein the activeagent is present in the form of a free base.

223. The dosage form of any one of points 217 to 221, wherein the activeagent is present in the form of a salt.

224. The dosage form of any one of points 217 to 223, wherein thecontrolled release carrier system further provides a decreased risk ofmisuse or abuse.

225. The dosage form of point 224, wherein said decreased risk of misuseor abuse is characterized by a low in vitro solvent extractability valueof the active agent from the dosage form.

226. The dosage form of point 224, wherein said decreased risk of misuseor abuse is characterized by the absence of any significant effect onabsorption of the active agent from the dosage form upon co-ingestion ofthe dosage form and alcohol by a subject.

227. The dosage form of point 225, wherein said decreased risk of misuseor abuse is further characterized by the absence of any significanteffect on absorption of the active agent from the dosage form uponco-ingestion of the dosage form and alcohol by a subject.

228. The dosage form of any one of points 217 to 227, wherein the invivo absorption of the active agent from the dosage form is enhancedupon administration of the dosage form with food.

229. An oral pharmaceutical dosage form comprising oxycodone and acontrolled release carrier system, wherein said pharmaceutical dosageform is abuse-resistant and, when dosed on a twice per day (BID) dosingschedule for a dosing interval of 5 days, provides a percent fluctuation(PF) ranging between about 85% and 115%.

230. The dosage form of point 229, wherein the PF ranges between about95% and 100%.

231. The dosage form of any of points 229 or 230, wherein the dosageform provides effective pain relief for at least 12 hours.

232. The dosage form of any of points 229 to 231, wherein the dosageform is further characterized by the absence of any significant effecton absorption of the oxycodone from the dosage form upon co-ingestion ofthe dosage form and alcohol by a subject.

233. The dosage form of any of points 229 to 232, wherein the dosageform is further characterized by a low injectability potential.

234. The dosage form of any of points 229 to 233, wherein the dosageform is not susceptible to common forms of abuse comprising injection,inhalation (crushing and sniffing) and volatilization (smoking).

235. An oral pharmaceutical dosage form comprising oxycodone and acontrolled release carrier system, wherein said pharmaceutical dosageform is abuse-resistant and exhibits an Abuse Quotient (AQ) value ofless than 10 when taken intact and with water as intended.

236. An oral pharmaceutical dosage form comprising oxycodone and acontrolled release carrier system, wherein said pharmaceutical dosageform is abuse-resistant and exhibits an Abuse Quotient (AQ) value ofless than 30 when taken after physical crushing and with 80 proofalcohol.

237. An oral pharmaceutical dosage form comprising oxycodone and acontrolled release carrier system, wherein said pharmaceutical dosageform is abuse-resistant and exhibits an Abuse Quotient (AQ) value ofless than about 25 when taken intact and after holding the dosage formin the buccal cavity for 10 minutes before swallowing.

238. An oral pharmaceutical dosage form comprising oxycodone and acontrolled release carrier system, wherein said pharmaceutical dosageform is abuse-resistant and exhibits an Abuse Quotient (AQ) value ofless than 35 when taken after vigorous chewing prior to swallowing.

239. The dosage form of any of points 235 or 238, wherein the dosageform provides effective pain relief for at least 12 hours.

240. The dosage form of any of points 235 to 239, wherein the dosageform is further characterized by a low injectability potential.

241. The dosage form of any of points 235 to 240, wherein the dosageform is not susceptible to common forms of abuse comprising injection,inhalation (crushing and sniffing) and volatilization (smoking).

242. An oral pharmaceutical dosage form comprising a pharmacologicallyactive agent, wherein the agent is an opioid, a central nervous system(CNS) depressant or a CNS stimulant, and a controlled release carriersystem which comprises:

-   -   (a) a high viscosity liquid carrier material (HVLCM),    -   (b) a network former,    -   (c) a rheology modifier,    -   (d) a hydrophilic agent; and    -   (e) a solvent;

wherein: the HVLCM is sucrose acetate isobutyrate (SAM); the networkformer is selected from cellulose acetate butyrate (CAB), celluloseacetate phthalate, ethyl cellulose, hydroxypropylmethyl cellulose andcellulose triacetate; the rheology modifier is selected from isopropylmyristrate (IPM), caprylic/capric triglyceride, ethyl oleate, triethylcitrate, dimethyl phthalate and benzyl benzoate; the hydrophilic agentis selected from hydroxyethylcellulose (HEC), hydroxypropylcellulose,carboxymethylcellulose, polyethylene glycol and polyvinylpyrrolidone;and the solvent is selected from triacetin, N-methyl-2-pyrrolidone,2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate andglycofurol.

243. The dosage form of point 242, wherein the pharmacologically activeagent is selected from oxycodone, oxymorphone, hydrocodone,hydromorphone, as free base or as pharmaceutically acceptable saltsthereof.

244. The dosage form of point 243, wherein (a) the HVLCM is SAM, (b) thenetwork former is CAB, (c) the rheology modifier is IPM, (d) thehydrophilic agent is HEC, and (e) the solvent is triacetin.

245. The dosage form of any one of points 242 to 244, which comprises(a) from 1.3 to 35 wt % of the pharmacologically active agent, (b) from2 to 10 wt % of the network former, (c) from 0.1 to 20 wt % of therheology modifier, (d) from 1 to 8 wt % of the hydrophilic agent, (e)from 10 to 40 wt % of the solvent, and (f) from 30 to 60 wt % of theHVLCM.

246. The dosage form of any one of points 242 to 245, wherein thecontrolled release carrier system further comprises a viscosityenhancing agent.

247. The dosage form of point 246, wherein the viscosity enhancing agentis a silicon dioxide.

248. The dosage form of any one of points 242 to 247 further comprisinga stabilizer agent.

249. The dosage form of point 248, wherein the stabilizer agent isbutylhydroxyl toluene (BHT).

250. The dosage form of any one points 242 to 249, which provides atleast 8 hours of substantially constant in vitro release of the activeagent when tested in an USP Type II Dissolution Apparatus modified witha stainless steel stationary basket assembly using a paddle speed of 100rpm and 0.1N HCl dissolution media containing 0.5% sodium laurylsulfate; and 20% or less of said active agent is extracted from saiddosage form after 1 hour at ambient temperature using EtOH (100 proof)as the extraction solvent.

251. The dosage form of any one of points 242 to 250, wherein less than20% of the active agent is extracted after 60 minutes of extraction inethanol (100 proof) at ambient temperature and less than 30% isextracted after 60 minutes of extraction in ethanol (100 proof) at 60°C.

252. The dosage form of any one of points 242 to 251, wherein theformulation of the active agent and the carrier system is encapsulatedwithin a biodegradable capsule.

253. The dosage form of point 252, wherein the capsule comprisesgelatin, hydroxyethylcellulose or hydroxypropylmethylcellulose.

254. The dosage form of point 251 or 252, wherein the capsules arepackaged in unit dose blisters or multidose plastic bottles.

255. A process for the preparation of an oral pharmaceutical dosage formas defined in point 242, which process comprises:

-   -   (i) preheating the HVLCM;    -   (ii) mixing the solvent with the preheated HVLCM, thereby        forming a uniform solution of the HVLCM in the solvent;    -   (iii) dispersing the network former in the solution, thereby        dissolving the network former in the solution;    -   (iv) mixing from 5 to 30% of the rheology modifier or,        optionally, a solution of a stabilising agent and from 5 to 30%        of the rheology modifier with the formulation obtained in step        (iii);    -   (v) mixing the pharmacologically active agent with the        formulation obtained in step (iv);    -   (vi) mixing the hydrophilic agent with the formulation obtained        in step (v);    -   (vii) optionally, mixing a viscosity enhancing agent with the        formulation obtained in step (vi);    -   (viii) mixing the balance of the rheology modifier with the        formulation obtained in step (vi) or, if step (vii) is effected,        step (vii);    -   (ix) optionally, filling capsules with the formulation obtained        in step (viii); and    -   (x) optionally, packaging the filled capsules into unit dose        blisters or multidose plastic bottles.

256. A process for the preparation of an oral pharmaceutical dosage formas defined in point 242, which process comprises:

-   -   (i) preheating the HVLCM;    -   (ii) mixing the solvent with the preheated HVLCM, thereby        forming a uniform solution of the HVLCM in the solvent;    -   (iii) optionally, mixing a solution of a stabilising agent and        from 5 to 30% of the rheology modifier with the solution        obtained in step (ii);    -   (iv) mixing the rheology modifier or, if step (iii) is effected,        the balance of the rheology modifier with the solution obtained        in step (ii) or (iii);    -   (v) optionally, mixing a viscosity enhancing agent with the        formulation obtained in step (iv);    -   (vi) dispersing the network former in the solution obtained in        step (iv) or, if step (v) is effected, step (v), thereby        dissolving the network former in the solution;    -   (vii) mixing the pharmacologically active agent with the        formulation obtained in step (vi);    -   (viii) mixing the hydrophilic agent with the formulation        obtained in step (vii);    -   (ix) optionally, filling capsules with the formulation obtained        in step (viii); and    -   (x) optionally, packaging the filled capsules into unit dose        blisters or multidose plastic bottles.

257. An oral pharmaceutical dosage form obtainable by a process asdefined in point 255 or 256.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1C depict the lab-scale manufacturing processes (ProcessSchemes 1-3) described in Example 1, FIG. 1D depicts the GMPmanufacturing process (Process Scheme 6) described in Example 1a, FIG.1E depicts the GMP manufacturing process (Process Scheme 7) described inExample 1b, and FIGS. 1F and 1G depict the GMP manufacturing processes(Process Schemes 8 and 9) described in Example 1c.

FIG. 2 depicts the commercial-scale manufacturing processes (ProcessSchemes 4-5) described in Example 2.

FIG. 3 is a pictorial representation of the modified dissolution vesseland paddle described in Example 3.

FIG. 4 shows the in vitro release performance of Test Capsules at 10, 20and 40 mg strength as described in Example 3a.

FIGS. 5A-5C show the results from the in vitro dissolution study of 5 mgstrength Test Capsules as described in Example 3b.

FIGS. 6A-6C show the results from the in vitro dissolution study of 20mg strength Test Capsules as described in Example 3b.

FIGS. 7A-7C show the results from the in vitro dissolution study of 40mg strength Test Capsules as described in Example 3b.

FIG. 8 shows the mean dissolution data results from the in vitrodissolution study of HMH Test Capsules as described in Example 3d.

FIGS. 9A and 9B show the mean dissolution data results from the in vitrodissolution study of HCB1 and HCB2 Test Capsules as described in Example3e.

FIGS. 10A and 10B show the mean dissolution data results from the invitro dissolution study of OMH1-OMH10 Test Capsules as described inExample 3f

FIG. 11 shows the mean dissolution data results from the in vitrodissolution study of AMP1-AMP3 Test Capsules as described in Example 3g.

FIGS. 12A and 12B show the mean dissolution data results from the invitro dissolution study of MPH1-MPH6 Test Capsules as described inExample 3h.

FIG. 13 shows the overall kinetics of active agent extraction from TestCapsules and Control tablets in a panel of household solvents at ambienttemperature (RT) in the in vitro abuse-resistance tests described inExample 4a.

FIG. 14 shows the overall kinetics of active agent extraction from TestCapsules and Control tablets in a panel of household solvents atelevated temperature (60° C.) in the in vitro abuse-resistance testsdescribed in Example 4a.

FIG. 15 shows the extraction results from Test Capsules compared againsta SR Control in a panel of household solvents (vinegar, coal soft drink,hot tea and saturated baking soda solution) obtained in the in vitroabuse-resistance tests described in Example 4b.

FIG. 16 shows the extraction results from Test Capsules compared againsta SR Control in a panel of aqueous buffers (pH1-pH12) obtained in the invitro abuse-resistance tests described in Example 4b.

FIG. 17 shows the extraction results from physically disrupted TestCapsules compared against a physically disrupted SR Control and thenextracted in a panel of household solvents (hot and cold water, strongacid and 100 proof ethanol) obtained in the in vitro abuse-resistancetests described in Example 4b.

FIG. 18 shows the extraction results from microwaved Test Capsulescompared against a SR Control and then extracted in a panel of householdsolvents (water, strong acid and 100 proof ethanol) obtained in the invitro abuse-resistance tests described in Example 4b.

FIG. 19 shows the volatilization results from Test Capsules against a SRControl obtained in the in vitro abuse-resistance test described inExample 4d.

FIG. 20 shows the mean linear plasma concentration-time curves of activeagent in the clinical trial study described in Example 7a.

FIG. 21 depicts the mean linear plasma concentration-time curves ofactive agent in the clinical trial study described in Example 7b.

FIG. 22 shows the mean linear plasma concentration-time curves of activeagent in the clinical trial study described in Example 7c.

FIG. 23 shows the results from the dose proportionality test of TestCapsules containing oxycodone at dosage strengths 5, 10, 20 and 40 mg asobtained in the clinical trial study described in Example 7c.

FIGS. 24 and 25 show the results of the in vivo abuse-resistance testcomparing a SR Control tablet containing 10 mg oxycodone against animmediate release oxycodone dosage form as described in Example 8.

FIG. 26 depicts the mean linear plasma concentration-time curves ofactive agent in the clinical trial study described in Example 8.

FIGS. 27 and 28 show the results of the in vivo abuse-resistance testcomparing 40 mg Test Capsules against a SR Control tablet containing 40mg oxycodone and an immediate release oxycodone dosage form as describedin Example 8a.

FIG. 29 shows the results of the in vivo abuse-resistance test of 40 mgTest Capsules containing oxycodone after being held in the buccal cavityas described in Example 8b.

FIG. 30 shows the results of the in vivo abuse-resistance test of 40 mgTest Capsules containing oxycodone taken either whole or after vigorousmastication as described in Example 8.

FIG. 31 depicts the mean linear plasma concentration-time curves ofactive agent in the in vivo abuse-resistance study described in Example8d.

FIG. 32 shows the mean plasma concentration of oxcodone (0-6 hour) afteringestion of 40 mg Test Capsules containing oxycodone when taken withwater, or with 4%, 20% or 40% ethanol as described in Example 8d.

FIG. 33 shows the mean linear plasma concentration-time curve ofamphetamine from Test Capsules administered in the clinical trial studydescribed in Example 11.

FIG. 34 depicts the chemical structure of sucrose acetate isobutyrate(SAIB).

DETAILED DESCRIPTION

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified carrier materials or process parameters as such may, ofcourse, vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments of theinvention only, and is not intended to be limiting.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a non-polymeric carrier material” includes a mixture oftwo or more such carrier materials, reference to “a solvent” includes amixture of two or more such solvents, reference to “an active agent”includes mixtures of two or more such agents, and the like.

In our earlier U.S. Patent Application, Publication No. US 2004/0161382,“Oral Drug Delivery System”, hereinafter referred to as the “382Publication”, we describe certain pharmaceutical dosage forms anddrug-delivery devices suitable for oral delivery of pharmacologicallyactive agents. These novel dosage forms and devices feature a uniquecombination of pharmaceutical excipients including an HVLCM, a networkformer, and an optional rheology modifier and/or a solvent that togetherprovide a controlled release carrier system. The controlled releasecarrier system is loaded with an active agent of interest, and willrelease the same over a period of time when in an aqueous environment,and in particular, an environment similar to that of the GI tract of amammal. The controlled release carrier system can further provide theadded benefit of enhanced abuse-resistance, wherein the carrier systemresists various physical disruption and other in vitro extractiontechniques (e.g., extraction into ethanol, water or other commonsolvents) that could be employed by someone wishing to disable thecontrolled release function of the system to access substantially all ormost of the sequestered active agent in an immediate release form thatcan be ingested, inhaled or injected to provide a euphoric effect. The382 Publication therefore describes a number of controlled releasecarrier systems that can be used to produce oral dosage forms ordelivery devices that provide desirable controlled release kineticsand/or abuse-resistance characteristics.

It is a primary object of the present invention to provide for improvedpharmaceutical dosage forms and drug-delivery devices suitable for oraldelivery of pharmacologically active agents, where such improved dosageforms and delivery devices are based upon the controlled release carriersystems described in the 382 Publication. In this regard, there hasremained a need in the art to provide a controlled release carriersystem that provides all of the benefits of those described in the 382Publication as well as providing enhanced safety features and/orabuse-resistance properties in addition to enhanced in vivopharmacological performance. One of the key hindrances facing theskilled person desiring to provide such a controlled release carriersystem resides in the very nature of the carrier system itself. Moreparticularly, the unique controlled release carrier system isresponsible for in vivo pharmacological performance, where the activeagent must be delivered from the system by diffusion from the system asit transits the GI tract. This same controlled release carrier system isalso responsible for the in vitro abuse-resistance and in vivo safetyperformance, that is, the carrier system must prevent active agent fromleaving the system when contacted with very efficient aqueous solventsand/or prolonged exposure to aqueous environments having a low or highpH. Thus, manipulations that can be made to the controlled releasesystem in order to, for example, increase overall delivery efficiency(AUC) or to provide for extended release rates (manipulations designedto increase release of the active agent from the controlled releasecarrier system) typically will frustrate the in vitro abuse-resistanceand in vivo safety performance of that same system. This is because,generally, formulation manipulations that increase C_(max) or decreaseT_(max) can frustrate abuse-resistance by allowing more/fasterextractability (e.g., changes designed to increase rate/extent of invivo drug release also increase rate/extent of in vitro drug releasewhen attempts are made to defeat the controlled release mechanism of adosage form). The term “AUC” means the area under the curve obtainedfrom an in vivo assay in a subject by plotting blood plasmaconcentration of the active agent in the subject against time, asmeasured from the time of administration, to a time “T” afteradministration. The time T will correspond to the delivery period of theactive agent to a subject. In like manner, manipulations that can bemade to the controlled release system in order to enhance in vitroabuse-resistance and in vivo safety performance (manipulations designedto decrease release of active agent from the controlled release carriersystem) typically will frustrate the in vivo pharmacological performanceof that same system. As used throughout this specification and theattached claims, the terms “abuse-resistance” and abuse-resistant” arecompletely interchangeable with the related terms “abuse-deterrence” and“abuse-deterrent”, as well as “tamper-resistance” and“tamper-resistant”, and “extraction-resistance” and“extraction-resistant” and thus mean exactly the same thing.

Accordingly, in one aspect of the invention, an abuse-resistant oralpharmaceutical dosage form is provided that comprises apharmacologically active agent in a controlled release carrier system.The subject dosage form is characterized in that the controlled releasecarrier system provides for controlled in vivo release of the agentcharacterized in that the individual steady state C_(min)/C_(max)variance within an interdose interval is less than or equal to theTherapeutic Index of the subject active agent. By “abuse-resistant”,herein, it is meant that the dosage form is resistant to extraction inethanol (80 or 100 proof) such that: less than about 20%, preferablyless than about 15% and more preferably less than about 10 to 11% of theactive agent is extracted after 60 minutes of extraction in 100 proofethanol at ambient temperature (RT); less than about 30%, morepreferably less than about 28% and more preferably less than about 25 to27% of the active agent is extracted after 60 minutes of extraction in100 proof ethanol at 60° C.; less than about 20%, preferably less thanabout 15% and more preferably less than about 12 to 13% of the activeagent is extracted after 60 minutes of extraction in 80 proof ethanol atambient temperature (RT); and less than about 40%, preferably less thanabout 35% and more preferably less than about 30 to 32% of the activeagent is extracted after 180 minutes of extraction in 80 proof ethanolat ambient temperature (RT). By the term “ambient temperature”, usedinterchangeabley herein with “room temperature” and/or “RT”, is meantthe normal temperature of a working area or laboratory and ranges fromabout 18 to 25° C., and is more particularly used herein to denote anormal temperature of 25° C. Suitable in vitro test methodology,techniques, apparatus and equipment to determine if a dosage form isproperly resistant to extraction in ethanol are described below inExample 4.

In certain preferred embodiments, the “abuse-resistant” dosage form isalso resistant to extraction in a panel of common household solvents,that is, the dosage form is further resistant to extraction in one ormore of the following: (a) resistant to extraction in cola soft drinks(pH about 2.5) such that less than 30%, preferably less than about 25%and more preferably less than about 22 to 23% of the active agent isextracted after 60 minutes of extraction in the cola soda at ambienttemperature (RT) and/or less than about 50%, preferably less than about48%, and more preferably less than about 42 to 46% is extracted after 60minutes of extraction in the cola soda at 60° C.; (b) resistant toextraction in household vinegar (pH about 2.5) such that less than 20%,preferably less than about 15% and more preferably less than about 11 to13% of the active agent is extracted after 60 minutes of extraction inthe vinegar at ambient temperature (RT) and/or less than about 25%,preferably less than about 23%, and more preferably less than about 18to 21% is extracted after 60 minutes of extraction in the vinegar at 60°C.; or (c) resistant to extraction in a saturated baking soda solution(pH about 8.5) such that less than 20%, preferably less than about 15%and more preferably less than about 10 to 14% of the active agent isextracted after 60 minutes of extraction in the saturated baking sodasolution at ambient temperature (RT) and/or less than about 27%,preferably less than about 25%, and more preferably less than about 20to 24% of the active agent is extracted after 60 minutes of extractionin the saturated baking soda solution at 60° C. Here again, suitable invitro tests to determine if a dosage form is properly resistant toextraction in these additional household solvents are described below inExample 4.

In certain other preferred embodiments, the “abuse-resistant” dosageform is also characterized by having a low injectability potential.Injectability potential of a dosage form can be assessed using standardtesting methods, and in particular using the testing methods describedin Example 4c below, wherein both “syringeability” and “injectability”of a test formulations are determined. In this regard, thecharacteristics of an injectable suspension are defined assyringeability and injectability. Syringeability pertains to the abilityof a suspension to be drawn into an empty syringe through a hypodermicneedle, while injectability address the ability of a suspension to bepushed from a pre-filled syringe through a hypodermic needle. Bothcharacteristics depend upon the viscosity and physical characteristicsof a test formulation. A formulation or dosage form containing thatformulation will will have a “low injectability potential” if thesyringeability and/or injectability of that formulation is low. Inrelated embodiments, the “abuse-resistant” dosage form is alsocharacterized by not being susceptible to common forms of abusecomprising injection, inhalation (crushing and sniffing) andvolatilization (smoking). Standard tests for assessing thesusceptability of a particular dosage form to these forms of abuse areknown in the art including, for example, the tests described in Examples4 and 8 below. In still further related embodiments, the“abuse-resistant” dosage form is also characterized by having: an AbuseQuotient (AQ) value of less than 10 when taken intact and with water asintended; an AQ value of less than 30 when taken after physical crushingand with 80 proof alcohol; an AQ value of less than about 25 when takenintact and after holding the dosage form in the buccal cavity for 10minutes before swallowing; and/or an AQ) value of less than 35 whentaken after vigorous chewing prior to swallowing. The Abuse Quotient(AQ) can be used as a method to express the attractiveness for abuse ofa formulation/dosage form. The AQ takes into account the observationthat increasing C_(max) and decreasing T_(max) increases theattractiveness of a particular dosage form for abuse. Represented as aformula, AQ=C_(max)/T_(max). AQ is a dose dependent metric as C_(max)varies with dose. The AQ for any dosage form under normal or underabuse-conditions can be assessed using standard testing methods known tothe skilled person including, for example, the test methods describedbelow in Example 8.

By “provides for controlled in vivo release of the agent characterizedin that the individual steady state C_(min)/C_(max) variance within aninterdose interval is less than or equal to the Therapeutic Index of theactive agent”, it is meant herein that, at steady state, the controlledrelease carrier system provides for optimum therapy in methods oftreatment that use repetitive administration of the dosage forms of thepresent invention. An “interdose interval;” refers to the period of timebetween a single administration of dosage form(s) and the nextsubsequent administration in a repetitive administration regimen (e.g.,if given every 24 hours (QD), the interdose interval would be the 24hours between dosing, if given every 12 hours (BID), it would be the 12hours between dosing, and the like). In this regard, to assess optimumdosing for a particular active agent of interest, a “Therapeutic Index”can be defined in terms of plasma concentration (systemic concentration)such that the Therapeutic Index equals the ratio of C*_(max)/C*_(min),where “C*_(max)” and “C*_(min)” are the maximum and minimum desiredplasma concentrations, respectively, that is, the maximum desired plasmaconcentration being the point above which the active agent would havetoxic affect, and the minimum desired plasma concentration being thepoint below which the active agent no longer provides the desiredpharmacological effect. See Theeuwes et al. (1977) Journal ofPharmaceutical Sciences 66(10):1388-1392. These maximal and minimalplasma concentration ranges of course relate to the dose at the repeatdosage amount, wherein an effective dose is generally the effective AUC(at steady state). The Therapeutic Index for any particular active agentof interest can be readily ascertained by the skilled person. It isunderstood that the Therapeutic Index may vary from person to person andmay vary in one person over time as the disease progresses or conditionsof treatment change. In general for opioids, patients become moretolerant to the drug as the level of pain increases and higher doses areneeded. Physicians will therefore adjust the dose over time. It is,however, very desirable to have a dosage form with fluctuationindex=C_(max)/C_(min) that is consistent and reproducible such that onlythe dose which gives rise to the average plasma level or AUC at steadyneeds to be adjusted to achieve optimum treatment.

For the dosage forms of the present invention, the controlled releasecarrier system provides for consistent and reproducible controlledrelease of the active agent such that the variance (ratio) of themeasured maximum and minimum plasma concentration extremes at steadystate (C_(max) and C_(min)), that is, individual steady stateC_(min)/C_(max) variance, will be less than or equal to the TherapeuticIndex for that particular active agent when dosed at the therapeuticallyeffective dose. In some cases, the individual steady stateC_(min)/C_(max) variance within an interdose interval is particularlylow, that is, less than or equal to about 2 to 3. In preferredembodiments, the individual steady state C_(min)/C_(max) variance withinan interdose interval is about 2 or less. In other cases, for examplewhere the Therapeutic Index for the active agent is substantiallylarger, the individual steady state C_(min)/C_(max) variance within aninterdose interval may be larger, for example about 5 to 6, or evengreater; however, release from the dosage forms of the present inventionis preferably much better controlled and thus provide for particularlylow variance regardless of the size of the Therapeutic Index. Theability of a controlled release carrier system to provide for controlledin vivo release of the agent characterized in that the individual steadystate C_(min)/C_(max) variance within an interdose interval is less thanor equal to the Therapeutic Index of the active agent can be readilydetermined by the skilled person by using standard in vitro dissolutiontesting, particularly the in vitro dissolution methods set forth inExample 4 below, and then applying an IVIVC transformation function suchas those set forth in Example 6 below to determine anticipated in vivovariability over the duration of controlled release for that dosageform. In addition to these in vitro testing methods, the ability of acontrolled release carrier system to provide for controlled in vivorelease of the agent characterized in that the individual steady stateC_(min)/C_(max) variance within an interdose interval is less than orequal to the Therapeutic Index of the active agent can be readilydetermined by the skilled person by using standard in vivopharmacological testing methods such as those described below inExamples 7 and 9-11.

As an alternative, the controlled release carrier systems of the presentinvention can provide for consistent and reproducible controlled releaseof the active agent characterized by having a low degree of flucuationat steady state. Accordingly, in certain preferred embodiments of theinvention, the abuse-resistant oral pharmaceutical dosage forms of thepresent invention comprise a controlled release carrier system thatprovides enhanced in vivo pharmacokinetic performance, such as when thedosage form is continusoulsy administered on, e.g., a BID (twice daily)dosing schedule over a dosing interval sufficient to reach steady state(e.g., 5 days), the percent fluctuation (PF) will range from about 85%to 115%, prefereably, between about 95% and 100%. The PF value can beobtained using standard pharmacokinetic analysis of plasmaconcentration/time data obtained in a steady state testing format,whereinPF=100×(C_(min)−C_(max))/C_(average)=100×(C_(min)−C_(max))/(AUC_(0-τ)/τ,wherein τ=time. By “C_(max)” is meant the maximum concentration of anactive agent in the blood plasma of a subject, generally expressed asmass per unit volume, typically nanograms per milliliter. “C_(min)” ismeant the minimum concentration of an active agent in the blood plasmaof a subject, generally expressed as mass per unit volume, typicallynanograms per milliliter. AUC is the area under the plasmaconcentration-time curve from time=0 throughout a dosing interval (τ);calculated using the linear trapezoidal rule.

In certain other preferred embodiments of the invention, theabuse-resistant oral pharmaceutical dosage forms comprise a controlledrelease carrier system that can provide enhanced in vivo pharmacokineticperformance such as wherein the in vivo release of the active agent fromthe carrier system is substantially free from food effect, or whereinthe carrier system has a food effect such that the in vivo absorption ofthe active agent from the carrier system is actually enhanced whenadministered in the presence of food. In this regard, the physiologicalbehavior of the stomach is usually determined by whether it containsfood (fed state) or is empty (fasted state). In the fed state, food ismixed and partially digested in the distal stomach as the stomachundergoes contractions, helping to move materials into the main part ofthe stomach for further digestion. At the end of a digestive period, thestomach enters the fasting stage and begins a cycle called theinterdigestive myoelectric motor cycle. These changes in physiologicalbehavior, as well as certain concomitant chemical changes (e.g., pH) asthe stomach switches between fed and fasted states may give rise tovariability in the rate and/or amount of delivery of an active agentfrom an oral dosage form. More particularly, a variety offormulation-dependent food-induced absorption changes (hereinafter “foodeffect”) can occur with controlled release compositions. These changescan include decreases in the rate and/or extent, increases in the rateand/or extent when taken in fed or fasted states, and erratic orvariable absorption of active agent from a controlled releasecomposition such as differences in absorption when the composition istaken with low-fat or high-fat meals. In extreme cases, a controlledrelease composition can have a significant food effect such that whenthe composition is taken with food, or with different kinds of food(high fat versus low fat meals), there can be a significant increase inabsorption (dose dumping) that, with a highly potent active agent and/oran active agent with significant side effect potential, can cause adosage form to be unsafe. In these cases, that is, where a formulationexhibits a pronounced food effect, the dosing relative to meal intakemay be made part of the product labeling to assure consistent and safeabsorption. If the difference in both the rate and extent of absorptionof an active agent from an oral dosage form varies significantly when itis administered in a fed versus a fasted state, the dosage form ischaracterized as having a food effect. In some cases, a dosage form canhave a food effect wherein administration of the dosage form with foodwill enhance the bioavailability of the active agent. On the other hand,if there is not a significant difference in both the rate and extent ofabsorption of an active agent from an oral dosage form as between fedand fasted states, the dosage form is characterized as beingsubstantially free from a food effect (e.g., co-administration with foodmay still have an effect on the maximal plasma concentration of theactive agent).

The controlled release carrier systems of the present invention can beprovided such that they are characterized: as having a food effect(administration of the dosage form with food will have a significanteffect on both the rate and extent of absorption of an active agent,i.e., the rate of absorption is decreased and the extent of absorptionis increased); as having a consistent food effect (administration of thedosage form with food will effect both the rate and extent of absorptionof an active agent, however, there is not a significant difference orvariability in this food effect as between different types of meals ordiets); or as being substantially free from a food effect(administration of the dosage form with or without food does notsignificantly effect both the rate to maximal plasma concentration, orT_(max), and the extent of absorption of the active agent, or AUC,although co-administration with food may still have an effect on themaximal plasma concentration, or C_(max), of the active agent).Accordingly, as used herein, “absence from food effect” means that theratio of mean AUC fed/fasted is within the accepted 80% to 125%bioequivalence limits for pharmaceutical dosage forms, and the ratio ofmean T_(max) fed/fasted is likewise within the accepted 80% to 125%bioequivalence limits. In addition, as used herein, “enhanced in vivoabsorption” means that the ratio of mean AUC fed/fasted is at leastgreater than the 125% upper bioequivalence limit and the ratio of meanT_(max) fed/fasted is greater than the 125% upper bioequivalence limit.As used herein, a “consistent food effect” means that there is enhancedin vivo absorption and the ratio of mean AUC fed high-fat/fed low-fat iswithin the accepted 80% to 125% bioequivalence limits for pharmaceuticaldosage forms, and the ratio of mean T_(max) fed/fasted is likewisewithin the accepted 80% to 125% bioequivalence limits. By “C” is meantthe concentration of an active agent in the blood plasma of a subject,generally expressed as mass per unit volume, typically nanograms permilliliter. By “C_(max)” is meant the maximum concentration of an activeagent in the blood plasma of a subject, generally expressed as mass perunit volume, typically nanograms per milliliter, within a specified timeinterval “T” after administration of the active agent to a subject, or“T_(max)”. As used herein, “fasted” means that, under a clinical trialsetting, a dosage form is administered to a subject that has fastedovernight for at least 10 hours, fasted for an additional 4 hours afterdosage administration, and then received a standardized high-fat(breakfast) meal. As used herein, “fed” means that, under a clinicaltrial setting, a dosage form is administered to a subject immediatelyafter having ingested a high-fat or low-fat standardized meal. A“high-fat” standardized meal consists of 2 slices of toasted white breadspread with butter, two eggs fried in butter, two slices of bacon, 2 ozhash-browned potatoes, and 8 oz whole milk (approximately 33 g protein,58 to 75 g fat, 58 g carbohydrate, 870 to 1020 calories). A “low-fat”standardized meal consists of one slice of toasted white bread spreadwith butter or jelly, 1 oz dry cereal (corn flakes), 8 oz skim milk, 6oz orange juice, and one banana (approximately 17 g protein, 8 g fat,103 g carbohydrate, 583 calories). All of the above-describedpharmacokinetic values can be readily determined by the skilled personusing established in vivo clinical trail procedures such as thosedescribed below in Example 7. Reference may also be made to “Guidancefor Industry”, Food-Effect Bioavailability and Fed BioequivalenceStudies, US Dept Health and Human Services, FDA, Center for DrugEvaluation and Research (CDER), December 2002.

Accordingly, in one particularly preferred embodiment of the invention,an abuse-resistant oral pharmaceutical dosage form is provided thatincludes a pharmacologically active agent and a controlled releasecarrier system. The controlled release carrier system provides forcontrolled in vivo release of the agent characterized in that theindividual steady state C_(min)/C_(max) variance within an interdoseinterval is less than or equal to the Therapeutic Index of the activeagent, and the in vivo release of the active agent from the controlledrelease carrier system is substantially free from food effect. In oneaspect of the invention, the pharmacologically active agent is presentin the dosage form as a salt. In another aspect of the invention, theactive agent is an opioid salt. In another particularly preferredembodiment of the invention, an abuse-resistant oral pharmaceuticaldosage form is provided that includes a pharmacologically active agentand a controlled release carrier system. The controlled release carriersystem provides for controlled in vivo release of the agentcharacterized in that the individual steady state C_(min)/C_(max)variance within an interdose interval is less than or equal to theTherapeutic Index of the active agent, and the extent of the in vivoabsorption of the active agent from the controlled release carriersystem is enhanced upon administration of the dosage form with food. Inone aspect of the invention, the dosage form is characterized as havinga consistent food effect, such that the extent of in vivo absorption ofthe active agent from the controlled release carrier system is enhancedupon administration of the dosage form with food but there is not asignificant difference between various diets or meal intakes (fedhigh-fat and fed, low-fat states). In this regard, this particularembodiment of the invention is believed to be a safer and more effectivedosage form, since the bioavailability of active agent from the dosageform is enhanced by the food effect and yet this food effect isconsistent over a range of reasonable diets, has a low sensitivity tothe particular food actually ingested, and does not dose-dump onadministration concomitant with a heavy, high-fat meal. In certainpreferred embodiments, the active agent can be an opioid,CNS-depressant, or CNS-stimulant that has a particularly high potentialfor abuse, diversion or other misuse. Preferably, the active agent cancomprise an opioid, an amphetamine, or a methylphenidate, in each caseeither as a salt or as a free base. In one aspect of the invention, theactive agent is an opioid free base, particularly oxycodone free base.

The ability to manipulate a controlled release carrier system producedaccording to the invention in order to provide different food-effectperformance was assessed as follows. An exemplary controlled releaseformulation comprised of 40.1 wt % SAM; 29.7 wt % Triacetin; 17 wt %IPM; 6 wt % HEC; 5.25 wt % CAB; 2 wt % SiO₂ and 0.02 wt % BHT wasprepared and filled into a size 00 gelatin capsule. A dissolution test(Method 1 of Example 3, below) was set up using a modified USP Type IIdissolution apparatus, paddle speed of 100 rpm and temperaturecontrolled at 37° C. and a dissolution medium of 0.1N HCl and 0.5% SDS.Sample formulations were added and the entire mass removed at: 3, 6, 8,10, 12, 18, 24 and 36 hours. Morphology and weight changes in thesamples were evaluated (n=2) to assess ingress of water into theformulation over time. It was found that there was significant weightchange as a function of time, wherein significant weight loss wasobserved over the first 6 hours, and then weight gain occurring between8 and 10 hours. Next, the egress of the solvent (triacetin) over timewas assessed. Using the same testing parameters and sampling thedissolution medium over time, the results of the study indicated thatelution of Triacetin takes place within the first 3 hours during thetime in which water uptake into the formulation is slow. However, afterthe 3 hour point, water uptake is significantly increased. These resultsindicate that factors such as solubility of the active agent in theselected solvent and in water can have an effect on the release kineticsof the agent from the formulation, wherein an active agent with highsolubility in the solvent and low water solubility would be expected todisplay a quick onset (e.g., burst) of release during the first 6 to 8hours of delivery, followed by a leveling off or tapering of release ataround 12 hours; whereas an active agent with high water solubility andlow solubility in the solvent would like follow zero-order dissolutionprofile (substantially constant) over the delivery period. In order toassess this expectation, the sample controlled release formulation wasused to produce oral dosage forms containing oxycodone free base (highsolubility in Triacetin, low water solubility) and oxycodone in saltform (HCl, low solubility in Triacetin, high solubility in water), andthe exemplary formulations were assessed using the above-describeddissolution testing methodologies. The results of the study demonstratedthat the formulation containing the free base form of the active agentshowed strong initial release performance, with about 60 to 70% of thetotal active agent being released within the first twelve hours. Incontrast, the formulation containing the salt form of the active agentshowed a substantially constant release performance over the entire testduration, with a much slower onset of action and only about 20 to 30% ofthe total active agent being released within the first twelve hours.Accordingly, matching active agent solubility parameters with thecontrolled release formulation constituents can be used to speed up ordelay onset of action, and to enhance or decrease the total amount ofactive agent that will be absorbed from the dosage form over the dosinginterval.

In certain other preferred embodiments of the invention, theabuse-resistant oral pharmaceutical dosage forms comprise a controlledrelease carrier system that can provide enhanced in vivo pharmacokineticperformance such as wherein the in vivo release of the active agent fromthe carrier system is sufficient to provide for an individualC_(min)/C_(max) variance at steady state is less than or equal to about2 or 3. By “steady state” is meant the condition in which the amount ofan active agent present in the blood plasma of a subject does not varysignificantly over a prolonged period of time. By “C” is meant theconcentration of an active agent in the blood plasma of a subject,generally expressed as mass per unit volume, typically nanograms permilliliter. By “C_(max)” is meant the maximum concentration of an activeagent in the blood plasma of a subject, generally expressed as mass perunit volume, typically nanograms per milliliter, within a specified timeinterval “T” after administration of the active agent to a subject, or“T_(max)”. By “C_(min)” is meant the minimum concentration of drug inthe blood plasma of a subject, generally expressed as mass per unitvolume, typically nanograms per milliliter, within a specified timeinterval after administration of the active agent to a subject. Hereagain, each of these pharmacokinetic values can be readily determined bythe skilled person using established in vivo clinical trail proceduressuch as those described below in Example 7.

In still further preferred embodiments of the invention, theabuse-resistant oral pharmaceutical dosage forms include a controlledrelease carrier system that can provide enhanced in vivo pharmacokineticperformance such as wherein the in vivo release of an opioid analgesicagent from the carrier system is characterized by a T_(max) of at leastabout 4 hours after ingestion by the subject. In one aspect of theinvention, the opioid analgesic agent is present in the dosage form as afree base. In another aspect of the invention, the opioid analgesicactive agent is oxycodone in free base form. This enhanced in vivopharmacokinetic performance can be readily assessed by the skilledperson using established in vivo clinical trial procedures such as thosedescribed below in Example 7.

In certain other preferred embodiments of the invention, theabuse-resistant oral pharmaceutical dosage forms comprise a controlledrelease carrier system that can provide a decreased risk of misuse orabuse. An important advantage of the dosage forms disclosed herein isthat they have abuse-resistant characteristics and/or reduced risk ofdiversion. In this regard, the formulation contained within the dosageform (the controlled release carrier system and the active agent) isneither susceptible to common crushing, pulverization or attritiontechniques, nor susceptible to extraction using common householdsolvents such as ethanol. In addition, the formulation contained withinthe dosage form (the controlled release carrier system and the activeagent) is also not susceptible to common heat extraction techniques(e.g., microwaving), vaporization techniques (e.g., volatilization orsmoking), nor injection techniques due to very poor syringeabilityand/or injectability properties of the formulation. Specifically, sincean HVLCM is a highly viscous liquid, formulations containing HVLCMsavoid the possibility of crushing for the purpose of inhalation.However, in a particular aspect of the invention, enhanced safetyfeatures can further be provided by the controlled release carriersystem. In this regard, the subject dosage forms are characterized ashaving either one or both of the following enhanced safety features: thecontrolled release carrier system is characterized by a low in vitrosolvent extractability value of the active agent from the dosage form;and/or the carrier system is characterized by the absence of anysignificant effect on absorption of the active agent from the dosageform upon co-ingestion of the dosage form with ethanol by a subject, orupon chewing (masticating) or holding the tablet within the mouth(buccal cavity) instead of swallowing the dosage form whole as intended.This second feature, so-called “dose-dumping” is of critical concern toregulatory agencies concerned with the safety of potent analgesic agentssuch as opioids. This is because, unlike the standard concerns aboutintentional abuse, a patient may inadvertently take a controlled releasedosage form containing a high potency opioid with a glass of wine, or acocktail, or a child may find a dropped capsule and chew the same. Ifthis activity is enough to defeat the controlled release system, apotentially lethal dose of the opioid analgesic may be inadvertentlyadministered. In this regard, recently the Palladone® brand controlledrelease hydromorphone product was withdrawn from the US market for thissafety reason.

Accordingly, in certain particularly preferred embodiments of theinvention, an abuse-resistant oral pharmaceutical dosage form isprovided that comprises a controlled release carrier system that canprovide a decreased risk of misuse or abuse, wherein the carrier systemis characterized by the absence of any significant effect on absorptionof the pharmacologically active agent from the dosage form uponco-ingestion of the dosage form with ethanol by a subject. The abilityof a dosage form to avoid this dose-dumping effect can be assessed usingcarefully controlled in vivo human clinical trial methods such as thosedescribed below in Example 8. By “no significant effect”, it is meantthat both the C_(max) ratio and the AUC ratio of absorption of theactive agent from the dosage form when taken with water, or with 4%, 20%or 40% ethanol is within a range of about 0.8 to 1.2. In certainpreferred embodiments, the active agent can be an opioid,CNS-depressant, or CNS-stimulant that has a particularly high potentialfor abuse, diversion or other misuse. Preferably, the active agent cancomprise an opioid, an amphetamine, or a methylphenidate. In one aspectof the invention, the pharmacologically active agent is present in thedosage form as a free base. In another aspect of the invention, theactive agent is an opioid free base, particularly oxycodone in free baseform.

In another particularly preferred embodiment of the invention, anabuse-resistant oral pharmaceutical dosage form is provided thatcomprises a controlled release carrier system that can provide adecreased risk of misuse or abuse, wherein the carrier system ischaracterized by a low in vitro solvent extractability value of theactive agent from the dosage form. Suitable in vitro test methodology,techniques and apparatus to determine if a dosage form is properlycharacterized as having “a low in vitro solvent extractability value”are described below in Example 4. In summary, a test dosage form can beplaced within a suitable amount of a liquid that my be readily obtained,for example water, alcohol (ethanol), soft drinks, vinegar, baking sodasolutions, and the like. After a suitable time (and, for example, withsuitable agitation or application of heat), the liquid “extractionsolvent” can be tested for the presence of extracted active agent. Anynumber of such liquids can be assembled into a “panel” of extractionsolvents for the purposes of such testing. Accordingly, in thesepreferred embodiments, the “abuse-resistant” dosage form is resistant toextraction across a panel of common household solvents, that is, lessthan 30% of the starting active agent is extracted from the dosage formafter extraction in all the following solvents for 60 minutes at ambient(RT) temperature: cola soft drinks (pH about 2.5); household vinegar (pHabout 2.5); a saturated baking soda solution (pH about 8.5); and ethanol(100 proof). In certain preferred embodiments, the active agent can bean opioid, CNS-depressant, or CNS-stimulant that has a particularly highpotential for abuse, diversion or other misuse. Preferably, the activeagent can comprise an opioid, an amphetamine, or a methylphenidate. Inone aspect of the invention, the pharmacologically active agent ispresent in the dosage form as a free base. In another aspect of theinvention, the active agent is an opioid free base, particularlyoxycodone in free base form. In a particularly preferred embodiment ofthe invention, the carrier system is further characterized by theabsence of any significant effect on absorption of the pharmacologicallyactive agent from the dosage form upon co-ingestion of the dosage formwith ethanol by a subject.

In another particularly preferred embodiment of the invention, acontrolled release oral pharmaceutical dosage form is provided thatincludes an opioid active agent, where the dosage form provideseffective analgesia to a subject when dosed on a twice per day (BID)dosing schedule, and further where the dosage form has one or moreabuse-resistant performance features (that may be assessed, for example,using the methodology of Examples 4 and 8). As used herein, the term“controlled release” is used in its broadest sense to include anyphysical and/or chemical association of a dosage form (containing,including or consisting of a pharmaceutical formulation) with one ormore active agents that provides for a controlled release (e.g.,extended release, delayed release or a release performance that is inany other way attenuated or altered from immediate release) of theactive agent to become pharmacologically available in the system of arecipient. In addition, a dosage form provides “effective analgesia” toa subject when dosed on a twice per day (BID) dosing schedule whenadministration of such dosage form elicits alleviation (e.g.,amelioration, attenuation, reduction, diminishment, blockage, inhibitionor prevention) of at least one sign or symptom of a pain symptom,including symptoms of acute or chronic pain. The ability of a dosageform to provide for effective analgesia can be readily assessed by theskilled person using standard clinical trial techniques including thoseemployed in Example 7f.

In particular embodiments, the controlled release dosage forms providefor one or more of the following abuse-resistant performance features:(a) when exposed to extraction in 100 proof ethanol at room temperaturefor 5 minutes, the dosage form releases less than about 5% of theopioid, preferably less than about 2% of the opioid; (b) when exposed toextraction in vinegar at room temperature for 5 minutes, the dosage formreleases less than about 5% of the opioid, preferably less than about 2%of the opioid; (c) when exposed to extraction in saturated baking sodasolution at room temperature for 5 minutes, the dosage form releasesless than about 5% of the opioid, preferably less than about 2% of theopioid; (d) when exposed to extraction in a cola soft drink at roomtemperature for 5 minutes, the dosage form releases less than about 10%of the opioid, preferably less than about 5% of the opioid; (e) whenexposed to extraction in 100 proof ethanol at room temperature for 60minutes, the dosage form releases less than about 20% of the opioid,preferably less than about 11% of the opioid; (f) when exposed toextraction in vinegar at room temperature for 60 minutes, the dosageform releases less than about 20% of the opioid, preferably less thanabout 12% of the opioid; (g) when exposed to extraction in saturatedbaking soda solution at room temperature for 60 minutes, the dosage formreleases less than about 20% of the opioid, preferably less than about12% of the opioid; (h) when exposed to extraction in a cola soft drinkat room temperature for 60 minutes, the dosage form releases less thanabout 30% of the opioid, preferably less than about 22% of the opioid;(i) when exposed to extraction in 100 proof ethanol at 60° C. for 5minutes, the dosage form releases less than about 15% of the opioid,preferably less than about 11% of the opioid; (j) when exposed toextraction in vinegar at 60° C. for 5 minutes, the dosage form releasesless than about 15% of the opioid, preferably less than about 11% of theopioid; (k) when exposed to extraction in saturated baking soda solutionat 60° C. for 5 minutes, the dosage form releases less than about 15% ofthe opioid, preferably less than about 11% of the opioid; (l) whenexposed to extraction in a cola soft drink at 60° C. for 5 minutes, thedosage form releases less than about 45% of the opioid, preferably lessthan about 30% of the opioid; (m) when exposed to extraction in 100proof ethanol at 60° C. for 60 minutes, the dosage form releases lessthan about 33% of the opioid, preferably less than about 26% of theopioid; (n) when exposed to extraction in vinegar at 60° C. for 60minutes, the dosage form releases less than about 33% of the opioid,preferably less than about 20% of the opioid; (o) when exposed toextraction in saturated baking soda solution at 60° C. for 60 minutes,the dosage form releases less than about 33% of the opioid, preferablyless than about 23% of the opioid; (p) when exposed to extraction in acola soft drink at 60° C. for 60 minutes, the dosage form releases lessthan about 60% of the opioid, preferably less than about 45% of theopioid; (q) when exposed to extraction in a panel of extraction solventsincluding vinegar, hot tea, saturated baking soda and a cola soft drink,each at 25° C. for 60 minutes, releases less than about 20% of theopioid, preferably less than about 15% of the opioid; (r) when exposedto extraction in a panel of aqueous buffer extraction solutions rangingfrom pH 1 to pH 12, each at 25° C. for 60 minutes, releases less thanabout 15% of the opioid, preferably less than about 12% of the opioid;(s) when physically disrupted by crushing the dosage form and exposed toextraction in a panel of aqueous extraction solutions including water at25° C., water at 60-70° C., 0.1N HCL at 25° C., and 100 proof ethanol at25° C., each for 60 minutes, releases less than about 40% of the opioid,preferably less than about 35% of the opioid; and/or (t) when physicallydisrupted by microwaving the dosage form and then exposed to extractionin a panel of aqueous extraction solutions including water, 0.1N HCL,and 100 proof ethanol, each at 25° C. for 60 minutes, releases less thanabout 25% of said opioid, preferably less than about 20% of the opioid.All of these abuse-resistant performance features can be readilyassessed using standard techniques, such as the techniques described inExample 4. Alternatively, or in addition, the above-described controlledrelease dosage forms may provide one or more of the followingabuse-resistant performance features: (a) the dosage form is not subjectto dose dumping as a result of physical disruption of the controlledrelease formulation by chewing, holding in the buccal cavity, orco-ingestion of alcohol (e.g., 4% ethanol (beer), 20% ethanol (fortifiedwine), or 40% ethanol (spirits)); (b) the dosage form is not subject toinhalation abuse techniques (e.g., vaporization or smoking, or crushingand snorting); and/or (c) the dosage form is not subject to injectionabuse techniques (e.g., the formulation in the dosage form is notsyringeable and/or injectable). All of these abuse-resistant performancefeatures can be readily assessed using standard techniques, such as thetechniques described in Example 8.

In certain preferred embodiments, the opioid is oxycodone, oxymorphone,hydrocodone, or hydromorphone and can be present in either salt or freebase form. In one particularly preferred embodiment, the opioid isoxycodone.

The pharmacologically active agents that are included in theabuse-resistant oral pharmaceutical dosage forms of the presentinvention may include any type of biologically active compound orcomposition of matter which, when administered to an organism (human oranimal subject) induces a desired pharmacologic and/or physiologiceffect by local and/or systemic action. The term therefore encompassesand can be used interchangeably with those compounds or chemicalstraditionally regarded as drugs, biopharmaceuticals (including moleculessuch as peptides, proteins, nucleic acids), and vaccines. The termfurther encompasses those compounds or chemicals traditionally regardedas diagnostic agents.

Accordingly, examples of such biologically active compounds orcompositions of matter useful in the practice of the invention includeopioids, CNS depressants and stimulants, as well as proteins, hormones,chemotherapeutic agents, anti-nausea medication, antibiotics, antiviralsand other agents. One class of biologically active compounds that is ofparticular interest herein is the opioids class, which includesalfentanil, allylprodine, alphaprodine, anileridine, apomorphine,apocodeine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, codeine, cyclazocine, cyclorphen, cyprenorphine,desomorphine, dextromoramide, dextromethorphan, dezocine, diampromide,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,levophenacylmorphan, levomethorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, methylmorphine, metopon, morphine, myrophine,nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone,nalorphine, normorphine, norpipanone, ohmefentanyl, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, pholcodine, piminodine, piritramide,propheptazine, promedol, profadol, properidine, propiram, propoxyphene,remifentanyl, sufentanyl, tramadol, tilidine, naltrexone, naloxone,nalmefene, methylnaltrexone, naloxone methiodide, nalorphine,naloxonazine, nalide, nalmexone, nalbuphine, nalorphine dinicotinate,naltrindole (NTI), naltrindole isothiocyanate, naltriben (NTB),nor-binaltorphimine (nor-BNI), tapentadol, beta-funaltrexamine (b-FNA),BNTX, cyprodime, ICI-174,864, LY117413, MR2266, etorphine, DAMGO, CTOP,diprenorphine, naloxone benzoylhydrazone, bremazocine,ethylketocyclazocine, U50,488, U69,593, spiradoline, DPDPE,[D-Ala2,Glu4] deltorphin, DSLET, Met-enkephalin, Leu-enkephalin,B-endorphin, dynorphin A, dynorphin B, a-neoendorphin, or an opioidhaving the same pentacyclic nucleus as nalmefene, naltrexone,buprenorphine, levorphanol, meptazinol, pentazocine, dezocine, or theirpharmacologically effective esters or salts. Preferred opioids for usein the practice of the present invention include morphine, hydrocodone,oxycodone, codeine, fentanyl (and its relatives), hydromorphone,meperidine, methadone, oxymorphone, propoxyphene or tramadol, ormixtures thereof. More preferred opioids include oxycodone, oxymorphone,hydrocodone and hydromorphone. In regard to the preferred opioidoxycodone, it may be beneficial to provide formulations that have areduced level of peroxide degradation products such as alpha betaunsaturated ketones (ABUK). In such cases, the controlled releasecarrier system can be subjected to peroxide contaminant reduction and/orremoval techniques in accordance with known methods.

Other biologically active compounds or compositions of matter useful inthe practice of the invention include prochlorperazine edisylate,ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine,procainamide, amphetamine (all forms including dexamphetamine,dextroamphetamine, d-S-amphetamine, and levoamphetamine), benzphetamine,isoproternol, methamphetamine, dexmethamphetamine, phenmetrazine,bethanechol, metacholine, pilocarpine, atropine, methascopolamine,isopropamide, tridihexethyl, phenformin, methylphenidate (all formsincluding dexmethylphenidate, d-threo methylphenidate, and dl-threomethylphenidate), oxprenolol, metroprolol, cimetidine, diphenidol,meclizine, prochlorperazine, phenoxybenzamine, thiethylperazine,anisindone, diphenadione erythrityl, digoxin, isofurophate, reserpine,acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide,tolazamide, chlormadinone, phenaglycodol, allopurinol, aluminum aspirin,methotrexate, acetyl sulfisoxazole, erythromycin, progestins, estrogenicprogrestational, corticosteroids, hydrocortisone, hydrocorticosteroneacetate, cortisone acetate, triamcinolone, methyltesterone, 17beta.-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether,prednisolone, 17-hydroxyprogesterone acetate, 19-nor-progesterone,norgestrel, orethindone, norethiderone, progesterone, norgestrone,norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac,diclofenac, indoprofen, nitroglycerin, propranolol, metroprolol, sodiumvalproate, valproic acid, taxanes such as paclitaxel, camptothecins suchas 9-aminocamptothecin, oxprenolol, timolol, atenolol, alprenolol,cimetidine, clonidine, imipramine, levodopa, chloropropmazine,resperine, methyldopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of.alpha.-methyldopa hydrochloride, theophylline, calcium gluconateferrous lactate, ketoprofen, ibuprofen, cephalexin, haloperiodol,zomepirac, vincamine, diazepam, phenoxybenzamine, .beta.-blockingagents, calcium-channel blocking drugs such as nifedipine, diltiazen,verapamil, lisinopril, captopril, ramipril, fosimopril, benazepril,libenzapril, cilazapril cilazaprilat, perindopril, zofenopril,enalapril, indalapril, qumapril, and the like.

Still other biologically active compounds or compositions of matteruseful in the practice of the invention include immunosuppressants,antioxidants, anesthetics, chemotherapeutic agents, steroids (includingretinoids), hormones, antibiotics, antivirals, antifungals,antiproliferatives, antihistamines, anticoagulants, antiphotoagingagents, melanotropic peptides, nonsteroidal and steroidalanti-inflammatory compounds, antipsychotics, and radiation absorbers,including UV-absorbers, chemotherapeutic agents, anti-nausea medication,and the like. Thus, anti-infectives such as nitrofurazone, sodiumpropionate, antibiotics, including penicillin, tetracycline,oxytetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin,neomycin, polymyxin, gramicidin, chloramphenicol, erythromycin, andazithromycin; sulfonamides, including sulfacetamide, sulfamethizole,sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole, andanti-virals including idoxuridine; antiallergenics such as antazoline,methapyritene, chlorpheniramine, pyrilamine prophenpyridamine,hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone,dexamethasone 21-phosphate, fluocinolone, triamcinolone, medrysone,prednisolone, prednisolone 21-sodium succinate, and prednisoloneacetate; desensitizing agents such as ragweed pollen antigens, hay feverpollen antigens, dust antigen and milk antigen; vaccines such assmallpox, yellow fever, distemper, hog cholera, chicken pox, antivenom,scarlet fever, dyptheria toxoid, tetanus toxoid, pigeon pox, whoopingcough, influenzae rabies, mumps, measles, poliomyelitic, and Newcastledisease; decongestants such as phenylephrine, naphazoline, andtetrahydrazoline; miotics and anticholinesterases such as pilocarpine,esperine salicylate, carbachol, diisopropyl fluorophosphate, phospholineiodide, and demecarium bromide; parasympatholytics such as atropinesulfate, cyclopentolate, homatropine, scopolamine, tropicamide,eucatropine, and hydroxyamphetamine; sympathomimetics such asepinephrine; sedatives and hypnotics such as pentobarbital sodium,phenobarbital, secobarbital sodium, codeine, (a-bromoisovaleryl) urea,carbromal; psychic energizers such as 3-(2-aminopropyl) indole acetateand 3-(2-aminobutyl) indole acetate; tranquilizers such as reserpine,chlorpromayline, and thiopropazate; androgenic steroids such asmethyl-testosterone and fluorymesterone; estrogens such as estrone,17-.beta.-estradiol, ethinyl estradiol, and diethyl stilbestrol;progestational agents such as progesterone, megestrol, melengestrol,chlormadinone, ethisterone, norethynodrel, 19-norprogesterone,norethindrone, medroxyprogesterone and 17-.beta.-hydroxy-progesterone;humoral agents such as the prostaglandins, for example PGE₁, PGE₂ andPGF₂; antipyretics such as aspirin, sodium salicylate, and salicylamide;antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine bromide; antimalarials such as the 4-aminoquinolines,8-aminoquinolines, chloroquine, and pyrimethamine, antihistamines suchas diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, andchlorphenazine; cardioactive agents such as dibenzhydroflume thiazide,flumethiazide, chlorothiazide, and aminotrate; nutritional agents suchas vitamins, natural and synthetic bioactive peptides and proteins,including growth factors, cell adhesion factors, cytokines, andbiological response modifiers are all suitable for use herein as theactive agent. These and other active agents are readily available tothose of ordinary skill in the art and are described in detail byreferences such as: Pharmaceutical Sciences, by Remington, 14th Ed.,1979, published by Mack Publishing Co., Easton, Pa.; Medical Chemistry,3rd Ed., Vol. 1 and 2, by Burger, published by Wiley-Interscience, NewYork; and, Physician's Desk Reference, 56th Ed., 2002, published byMedical Economics Co., New Jersey.

The active agent can be present in the formulations used to make thedosage forms of the present invention in a neutral form, as a free baseform, or in the form of a pharmaceutically acceptable salt. The term“pharmaceutically acceptable salt,” as used herein, intends those saltsthat retain the biological effectiveness and properties of neutralactive agents and are not otherwise unacceptable for pharmaceutical use.Pharmaceutically acceptable salts include salts of acidic or basicgroups, which groups may be present in the active agents. Those activeagents that are basic in nature are capable of forming a wide variety ofsalts with various inorganic and organic acids. Pharmaceuticallyacceptable acid addition salts of basic active agents suitable for useherein are those that form non-toxic acid addition salts, i.e., saltscomprising pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Active agents thatinclude an amino moiety may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above. Suitablebase salts can be formed from bases which form non-toxic salts, forexample, aluminium, calcium, lithium, magnesium, potassium, sodium, zincand diethanolamine salts. See, e.g., Berge et al. (1977) J. Pharm. Sci.66:1-19.

In the abuse-resistant oral pharmaceutical dosage forms of the presentinvention, the pharmacologically active agent will be dissolved (fullyor partially) or dispersed within the controlled release carrier system.The phrase “dissolved or dispersed” is intended to encompass all meansof establishing a presence of the active agent in the subject controlledrelease carrier system and includes dissolution, dispersion, partialdissolution and dispersion, and/or suspension and the like. In addition,in certain embodiments of the invention wherein the active agent is in asolid particulate form suspended within the controlled release carriersystem, the active agent particulate may be pre-treated with amicronization process such as those described in Examples 1 and 2 belowto provide a particle population having a substantially homogeneousparticle size the bulk of which fall within the micron (μm) range.

The pharmacologically active agent, which can include one or moresuitable active agent, will be present in the formulation used to makethe present dosage forms in an amount of from about 95 to about 0.1percent by weight relative to the total weight of the formulation (wt%), in an amount of from about 40 to 1 wt %, in an amount of from about35 to 1.3 wt %, or in an amount of about 30 to 5 wt %, depending uponthe identity of the active agent, the desired dose required for thedosage form, and the intended use thereof. In certain preferredembodiments, the active agent is present in the formulation in an amountof about 1 to about 10 wt %, and can thus be loaded into a suitabledosage form to provide single dosages ranging from about 0.01 mg to 1000mg, or from about 0.1 mg to 500 mg, or from about 2 mg to 250 mg, orfrom about 2 mg to 250 mg, or from about 2 mg to 150 mg, or from about 5mg to 100 mg, or from about 5 mg to 80 mg. For certain preferredembodiments that include an opioid active agent, exemplary singledosages include, but are not limited to, 1, 2, 3, 5, 10, 15, 20, 30, 40,60, 80 100, and 160 mg. In other preferred embodiments that include aCNS depressant or CNS stimulant, exemplary single dosages include, butare not limited to, 5, 10, 15, 18, 20, 25, 27, 30, 36, 40, 50, 54, 60,70, 80 and 100 mg. The precise amount of active agent desired can bedetermined by routine methods well known to pharmacological arts, andwill depend on the type of agent, and the pharmacokinetics andpharmacodynamics of that agent.

The controlled release carrier systems that are employed in theabuse-resistant oral pharmaceutical dosage forms disclosed and claimedherein are formed by the combination of a High Viscosity Liquid CarrierMaterial (“HVLCM”), a network former, and a rheology modifier. An HVLCMis a non-polymeric, non-water soluble liquid material having a viscosityof at least 5,000 cP at 37° C. that will not crystallize neat underambient or physiological conditions. The term “non-water soluble” refersto a material that is soluble in water to a degree of less than onepercent by weight under ambient conditions. The term “non-polymeric”refers to esters or mixed esters having essentially no repeating unitsin the acid moiety of the ester, as well as esters or mixed estershaving acid moieties wherein functional units in the acid moiety arerepeated a small number of times (i.e., oligomers). Generally, materialshaving more than five identical and adjacent repeating units or mers inthe acid moiety of the ester are excluded by the term “non-polymeric” asused herein, but materials containing dimers, trimers, tetramers, orpentamers are included within the scope of this term. When the ester isformed from hydroxy-containing carboxylic acid moieties that can furtheresterify, such as lactic acid or glycolic acid, the number of repeatunits is calculated based upon the number of lactide or glycolidemoieties, rather than upon the number of lactic acid or glycolic acidmoieties, where a lactide repeat unit contains two lactic acid moietiesesterified by their respective hydroxy and carboxy moieties, and where aglycolide repeat unit contains two glycolic acid moieties esterified bytheir respective hydroxy and carboxy moieties. Esters having 1 to about20 etherified polyols in the alcohol moiety thereof, or 1 to about 10glycerol moieties in the alcohol moiety thereof, are considerednon-polymeric as that term is used herein. HVLCMs may becarbohydrate-based, and may include one or more cyclic carbohydrateschemically combined with one or more carboxylic acids. HVLCMs alsoinclude non-polymeric esters or mixed esters of one or more carboxylicacids, having a viscosity of at least 5,000 cP at 37° C., that do notcrystallize neat under ambient or physiological conditions, wherein whenthe ester contains an alcohol moiety (e.g., glycerol). The ester may,for example comprise from about 2 to about 20 hydroxy acid moieties.Various HVLCMs used with the present controlled release carrier systemsare described in U.S. Pat. Nos. 5,747,058; 5,968,542; and 6,413,536. Thepresent invention may employ any HVLCM described in these patents but isnot limited to any specifically described materials. The HVLCM istypically present in a dosage form according to the invention in anamount of from 30 to 60%, for example from 35 to 45%, by weight.

In certain preferred embodiments of the invention, the controlledrelease carrier system comprises Sucrose Acetate Isobutyrate (“SAIB”) asthe HVLCM. SAIB is a non-polymeric highly viscous liquid at temperaturesranging from −80° C. to over 100° C., it is a fully esterified sucrosederivative, at a nominal ratio of six isobutyrates to two acetates. Thechemical structure of SAIB is depicted herein as FIG. 34. The SAIBmaterial is available from a variety of commercial sources includingEastman Chemical Company, where it is available as a mixed ester thatdoes not crystallize but exists as a very highly viscous liquid. It is ahydrophobic, non-crystalline, low molecular weight molecule that iswater insoluble and has a viscosity that varies with temperature. Forexample, pure SAIB exhibits a viscosity of approximately 2,000,000centipoise (cP) at ambient temperature (RT) and approximately 600 cP at80° C. The SAIB material has unique solution-viscosity relationship inthat a SAIB solution established in a number of organic solvents has asignificantly lower viscosity value than the pure SAIB material, andtherefore the SAIB-organic solvent solutions render themselves capableof processing using conventional equipment such as mixers, liquid pumpsand capsule production machines. SAIB also has applications in drugformulation and delivery, for example as described in U.S. Pat. Nos.5,747,058; 5,968,542; 6,413,536; and 6,498,153. In the presentinvention, SAIB may be used as the HVLCM and may be present inquantities that vary significantly. For example, quantities of at leastabout 30, 35, 40, 50, 60, or from 61 to 99.9 percent by weight of theHVLCM, which can include one or more suitable HVLCM, relative to thetotal weight of the formulation (wt %) used to make the dosage form canbe used. Typically, SAIB is present in a dosage form according to theinvention in an amount of from 30 to 60% by weight, for example from 35to 45% by weight.

In certain circumstances, it may be beneficial to provide a SAIB carriermaterial having a lower peroxide level to avoid peroxide-baseddegradation of various components of the controlled release carriersystem and/or active agent. See, e.g., U.S. Patent ApplicationPublication Number US 2007/0027105, “Peroxide Removal From Drug DeliveryVehicle”. Various specific pharmaceutical formulations containing SAM atabout 40 wt % that are used to produce suitable dosage forms arediscussed in the examples.

A “rheology modifier”, as used herein, refers to a substance thatpossesses both a hydrophobic and a hydrophilic moiety. Rheologymodifiers used in the practice of the invention generally have alogarithm of octanol-water partition coefficient (“Log P”) of betweenabout −7 and +15, preferably between −5 and +10, more preferable between−1 and +7. In addition, the rheology modifier will typically have amolecular weight of around 1,000 daltons or less. Rheology refers to theproperty of deformation and/or flow of a liquid material, and rheologymodifiers are used to modify (lower) viscosity and (increase)flowability of the HVLCM and other constituents used in the controlledrelease carrier system, that is, to plasticize the HVLCM and otherconstituents. The rheology modifier may thus be a plasticizer, typicallya plasticizer for the HVLCM. Rheology modifiers that are useful hereininclude, for example, caprylic/capric triglyceride (Migliol 810),isopropyl myristate (“IPM”), ethyl oleate, triethyl citrate, dimethylphthalate, labrafil, labrasol, Gelucires, and benzyl benzoate. Incertain preferred embodiments of the invention, the rheology modifier isIPM. The IPM material is a pharmaceutically acceptable hydrophobicsolvent. The rheology modifier, which can include one or more suitablerheology modifier material, can be present in the formulations at fromabout 0.1 to about 20 percent by weight relative to the total weight ofthe formulation (wt %) used to produce the dosage forms of the presentinvention, preferably at from about 1 to about 18 wt %, and morepreferably at from about 2 to about 15 wt %.

A “network former” refers to a material or compound that forms a networkstructure when introduced into a liquid medium (such as a HVLCM or acontrolled release carrier system comprising an HVLCM). Network formersmay be added to the liquid formulation such that, upon exposure to anaqueous environment, they form a three dimensional network within theformulation. While not wishing to be bound by any particular theory, itis believed that the network former allows the formation of amicro-network within the formulation upon exposure to an aqueousenvironment. This micro-network formation appears to be due, at least inpart, to a phase inversion (e.g., a change in glass transitiontemperature, T_(g)) of the network former. The result is believed to bea skin or surface layer of precipitated network former at the interfacebetween the dosage form and the aqueous environment of the GI tract, aswell as the formation of a three-dimensional micro-network ofprecipitated network former within the dosage form. The network forweris selected so as to have good solubility in the selected solvent usedin the formulations, for example a solubility of between about 0.1 and20 wt %. Additionally, good network formers will typically have a Log Pbetween about −1 to 7. Suitable network formers include, for example,cellulose acetate butyrate (“CAB”), carbohydrate polymers, organic acidsof carbohydrate polymers and other polymers, hydrogels, celluloseacetate phthalate, ethyl cellulose, Pluronic, Eudragit, Carbomer,hydroxyl propyl methyl cellulose, other cellulose acetates such ascellulose triacetate, PMMA, as well as any other material capable ofassociating, aligning or congealing to form three-dimensional networksin an aqueous environment. A particularly preferred network former foruse in the practice of the invention is cellulose acetate butyrate grade381-20 BP (“CAB 381-20” available from Eastman Chemicals). CAB 381-20 isa non-biodegradible polymer material that has the following chemical andphysical characteristics: butyryl content of 36%, acetyl content of15.5%, hydroxy content of 0.8%, a melting point of 185-196° C., glasstransition temperature of 128° C., and a molecular weight number averageof 66,000 to 83,000. Preferably, if a CAB material is used in thepresent formulations, it should be subjected to an ethanol washing step(and subsequent drying step) prior to addition to the formulation inorder to remove potential contaminants therefrom. The network former,which can include one or more suitable network former materials, can bepresent in the formulations at from about 0.1 to about 20 percent byweight relative to the total weight of the formulation (wt %),preferably at from about 1 to about 18 wt %, more preferably at fromabout 2 to about 10 wt %, and even more preferably at from about 4 toabout 6 wt %.

In addition to the combination of the HVLCM, network former and rheologymodifier materials discussed above, the controlled release carriersystems that are employed in the abuse-resistant oral pharmaceuticaldosage forms disclosed and claimed herein can further include a numberadditional excipient materials including solvents, viscosity enhancingagents, hydrophilic agents, surfactants, and stabilizing agents.

The term “solvent”, as used herein, refers to any substance thatdissolves another substance (solute). Solvents may be used in thecontrolled release carrier systems of the present invention to dissolveone or more of the following constituents: HVCLMs; active agents;network formers; rheology modifiers; viscosity enhancing agents;hydrophilic agents; surfactants; and stabilizing agents. Preferably, thesolvent can dissolve both the HVLCM and the network former. In addition,materials that can serve as rheology modifiers in certain controlledrelease carrier systems can also serve the function as a solvent to oneor more constituent (e.g., the HVLCM, or the active agent), or servesolely as a solvent in other carrier systems. One example of such asolvent is IPM, which is a hydrophobic solvent. In one embodiment of theinvention, therefore, a dosage form may comprise both a hydrophilicsolvent and a hydrophobic solvent. Organic solvents suitable for usewith the present invention include, but are not limited to: substitutedheterocyclic compounds such as N-methyl-2-pyrrolidone (NMP) and2-pyrrolidone(2-pyrol); triacetin; esters of carbonic acid and alkylalcohols such as propylene carbonate, ethylene carbonate and dimethylcarbonate; fatty acids such as acetic acid, lactic acid and heptanoicacid; alkyl esters of mono-, di-, and tricarboxylic acids such as2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyl lactate,ethyl butyrate, diethyl malonate, diethyl glutonate, tributyl citrate,diethyl succinate, tributyrin, isopropyl myristate (IPM), dimethyladipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate,triethyl citrate, acetyl tributyl citrate, glyceryl triacetate; alkylketones such as acetone and methyl ethyl ketone; ether alcohols such as2-ethoxyethanol, ethylene glycol dimethyl ether, glycofurol and glycerolformal; alcohols such as benzyl alcohol, ethanol and propanol;polyhydroxy alcohols such as propylene glycol, polyethylene glycol(PEG), glycerin (glycerol), 1,3-butyleneglycol, and isopropylideneglycol (2,2-dimethyl-1,3-dioxolone-4-methanol); Solketal; dialkylamidessuch as dimethylformamide, dimethylacetamide; dimethylsulfoxide (DMSO)and dimethylsulfone; tetrahydrofuran; lactones such as ε-caprolactoneand butyrolactone; cyclic alkyl amides such as caprolactam; aromaticamides such as N,N-dimethyl-m-toluamide, and1-dodecylazacycloheptan-2-one; and the like; and mixtures andcombinations thereof. Preferred solvents include triacetin,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,propylene carbonate, and glycofurol. In one particular preferredembodiment, the solvent is triacetin which is a hydrophilic solvent. Thehydrophilic triacetin solvent can preferably be combined with the IPMrheology modifier which is a hydrophobic solvent to provide a solventhydrophobic/hydrophilic solvent system within the controlled releasecarrier system. The solvent, which can include one or more suitablesolvent materials, can be present in the formulations at from about 0.1to about 40 percent by weight relative to the total weight of theformulation (wt %), preferably at from about 1 to about 35 wt %, morepreferably at from about 10 to about 30 wt %, and even more preferablyat from about 15 to about 28 wt %.

A “viscosity enhancing agent” or “second viscosity enhancing agent” is amaterial that can be added to the controlled release carrier system inorder to increase the viscosity of the resulting carrier system.Viscosity enhancing agents can be selected to have good hydrogen bondingcapability, such as a bonding capability greater than or equal to oneper molecule. In certain cases, the viscosity enhancing agent has verylow to no significant solubility in the formulation. If the agent issoluble, then preferably the solubility is less than 50 wt %. Forinorganic or mineral viscosity enhancing agents, it is preferable if thematerial has a specific surface area greater than or equal to about 100m2/g. For those skilled in the use of pharmaceutical systems using anHVLCM, particularly SAM, it is generally known that as the viscosity ofthe controlled release system increases, e.g., as a solvent for theHVLCM leaves the system or by addition of a polymer material, release ofthe active agent from that carrier system will typically slow down sincethe HVLCM carrier matrix material has become more resistant to diffusionof the agent from the matrix material. Accordingly, it may becounter-intuitive for the skilled person to purposefully enhance(increase) the overall viscosity of the present controlled releasecarrier systems when it is desired to enhance the in vivopharmacological performance of such systems to, for example, extendand/or increase the release performance to increase bioavailability ofan active agent. However, it has been found that in certain dosage formsof the present invention, the addition of a viscosity enhancing agentcan be used to provide dosage forms having enhanced in vivopharmacological performance as well as enhanced safety features and/orabuse-resistance properties as required herein. Suitable viscosityenhancing agents include biodegradable and non-biodegradable polymermaterials. Non-limiting examples of suitable biodegradable polymers andoligomers include: poly(lactide), poly(lactide-co-glycolide),poly(glycolide), poly(caprolactone), polyamides, polyanhydrides,polyamino acids, polyorthoesters, polycyanoacrylates,poly(phosphazines), poly(phosphoesters), polyesteramides,polydioxanones, polyacetals, polyketals, polycarbonates,polyorthocarbonates, degradable polyurethanes, polyhydroxybutyrates,polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates,poly(malic acid), chitin, chitosan, and copolymers, terpolymers,oxidized cellulose, hydroxyethyl cellulose, or combinations or mixturesof the above materials. Suitable non-biodegradable polymers include:polyacrylates, ethylene-vinyl acetate polymers, cellulose and cellulosederivatives, acyl substituted cellulose acetates and derivatives thereofincluding cellulose acetate butyrate (CAB), which is also used herein asa network former, non-erodible polyurethanes, polystyrenes, polyvinylchloride, polyvinyl fluoride, polyvinyl (imidazole), chlorosulphonatedpolyolefins, polyethylene oxide, and polyethylene. Other suitableviscosity enhancing materials include stiffening agents such as claycompounds, including, talc, bentonite and kaolin, and metal oxidesincluding silicon dioxide, zinc oxide, magnesium oxide, titanium oxide,and calcium oxide. In one preferred embodiment of the invention, acolloidal silicon dioxide (Cab-O-Sil) is used as a viscosity enhancingagent in a controlled release carrier system that further contains CABas a network former. The colloidal silicon dioxide may further becharacterized as a thixtropic agent since it is thought to enhanceviscosity at resting conditions, which may be useful for productstability purposes, while also serving as viscosity thinning agent underconditions of mechanical stress which may be useful for controlledrelease performance. The viscosity enhancing agent, which can includeone or more suitable viscosity enhancing material, can be present in theformulations at from about 0.01 to about 10 percent by weight relativeto the total weight of the formulation (wt %) used to produce the dosageforms of the present invention, preferably at from about 0.1 to about 6wt %, and more preferably at from about 1 to about 2 wt %.

Materials that can be used as “hydrophilic agents” in the practice ofthe invention include those that have natural affinity for aqueoussystems. A material may be regarded as a hydrophilic agent for thepurposes of this invention if the material displays a water sorptionbetween about 10 to 100% (w/w). Hydrophilic agents will have a low Log Pvalue. As discussed herein above, there are a number of constituentsused to produce the controlled release carrier systems of the presentinvention that can be classed as a hydrophilic material (e.g., ahydrophilic solvent), or at least a material having a hydrophilicportion (e.g., a rheology modifier). Since the HVLCM material used inthe present carrier systems is hydrophobic, it may be useful to includeother materials in the carrier system that are hydrophilic in order toprovide a carrier system that is balanced to have both hydrophobic andhydrophilic characteristics. For example, it is believed that theinclusion of one or more hydrophilic agent in the controlled releasecarrier systems of the present invention may participate in the controlof active agent diffusion from the carrier system. Accordingly, suitablehydrophilic agents include, but are not limited to, sugars such assorbitol, lactose, mannitol, fructose, sucrose and dextrose, salts suchas sodium chloride and sodium carbonate, starches, hyaluronic acid,glycine, fibrin, collagen, polymers such as hydroxylpropylcellulose(“HPC”), carboxymethylcellulose, hydroxyethyl cellulose (“HEC”);polyethylene glycol and polyvinylpyrrolidone, and the like. In aparticularly preferred embodiment, a controlled release carrier systemis provided that includes HEC as a hydrophilic agent. The hydrophilicagent, which can include one or more suitable hydrophilic agentmaterial, can be present in the formulations at from about 0.1 to about10 percent by weight relative to the total weight of the formulation (wt%) used to produce the dosage forms of the present invention, preferablyat from about 1 to about 8 wt %, and more preferably at from about 3 toabout 6 wt %. The hydrophilic agent may alternatively constitute the“first viscosity enhancing agent” of an embodiment of the invention.

Materials that can be used as “surfactants” in the practice of theinvention include neutral and/or anionic/cationic excipients.Accordingly, suitable charged lipids include, without limitation,phosphatidylcholines (lecithin), and the like. Detergents will typicallybe a nonionic, anionic, cationic or amphoteric surfactant. Examples ofsuitable surfactants include, for example, Tergitol® and Triton®surfactants (Union Carbide Chemicals and Plastics);polyoxyethylenesorbitans, e.g., TWEEN® surfactants (Atlas ChemicalIndustries); polysorbates; polyoxyethylene ethers, e.g. Brij;pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate andsalts thereof; ampiphilic surfactants (glycerides, etc.); Gelucires(saturated polyglycolized glyceride (e.g., Gattefosse brand); and likematerials. Surfactants, which can include one or more suitablesurfactant material, can be present in the formulations at from about0.01 to about 5 percent by weight relative to the total weight of theformulation (wt %) used to produce the dosage forms of the presentinvention, preferably at from about 0.1 to about 5 wt %, and morepreferably at from about 0.1 to about 3 wt %.

Materials that can be used as stabilizing agents in the practice of theinvention include any material or substance that can inhibit or reducedegradation (e.g., by chemical reactions) of other substances orsubstances in the controlled release carrier system with which thestabilizer is mixed. Exemplary stabilizers typically are antioxidantsthat prevent oxidative damage and degradation, e.g., sodium citrate,ascorbyl plamitate, vitamin A, and propyl gallate and/or reducingagents. Other examples include ascorbic acid, vitamin E, sodiumbisulfite, butylhydroxyl toluene (“BHT”), BHA, acetylcysteine,monothioglycerol, phenyl-alpha-nathylamine, lecithin, and EDTA. Thesestabilizing materials, which can include one or more suitable suchmaterials, can be present in the formulations at from about 0.001 toabout 2 percent by weight relative to the total weight of theformulation (wt %) used to produce the dosage forms of the presentinvention, preferably at from about 0.01 to about 0.1 wt %, and morepreferably at from about 0.01 to about 0.02 wt %.

An oral pharmaceutical dosage form produced according to the inventionand comprising a pharmacologically active agent and a controlled releasecarrier system which comprises a HVLCM, a network former, a rheologymodifier, a hydrophilic agent and a solvent can thus contain: (a) from1.3 to 35 wt % such as 5 to 10 wt % of the pharmacologically activeagent; (b) from 2 to 10 wt % such as 4 to 6 wt % of the network former;(c) from 0.1 to 20 wt % for example 2 to 15 wt % of the rheologymodifier; (d) from 1 to 8 wt % for example 3 to 6 wt % of thehydrophilic agent; (e) from 10 to 40 wt % for example from 10 to 30 wt %of the solvent; and (f) from 30 to 60 wt % such as 35 to 45 wt % of theHVLCM. Typically, the HVLCM is sucrose acetate isobutyrate (SAIB); thenetwork former is selected from cellulose acetate butyrate (CAB),cellulose acetate phthalate, ethyl cellulose, hydroxypropylmethylcellulose and cellulose triacetate; the rheology modifier is selectedfrom isopropyl myristate (IPM), caprylic/capric triglyceride, ethyloleate, triethyl citrate, dimethyl phthalate and benzyl benzoate; thehydrophilic agent is selected from hydroxyethylcellulose (HEC),hydroxypropylcellulose, caboxymethylcellulose, polyethylene glycol andpolyvinylpyrrolidone; and the solvent is selected from triacetin,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,propylene carbonate and glycofurol. Preferably, the HVLCM is SAIB, thenetwork former is CAB, the rheology modifier is IPM, the hydrophilicagent is HEC, and the solvent is triacetin.

The controlled release carrier system can further comprise a viscosityenhancing agent such as silicon dioxide. The viscosity enhancing agentis typically present in an amount from 0.1 to 6 wt % such as 1 to 2 wt%.

In an alternative embodiment, an oral pharmaceutical dosage formproduced according to the invention and comprising a pharmacologicallyactive agent and a controlled release carrier system which comprises aHVLCM, a network former, a first viscosity enhancing agent, ahydrophilic solvent and a hydrophobic solvent, can contain: (a) from 1.3to 35 wt % such as 5 to 10 wt % of the pharmacologically active agent;(b) from 2 to 10 wt % such as 4 to 6 wt % of the network former; (c)from 1 to 8 wt % for example 3 to 6 wt % of the first viscosityenhancing agent; (d) from 10 to 40 wt % for example 10 to 30 wt % of thehydrophilic solvent; (e) from 0.1 to 20 wt % for example from 2 to 15 wt% of the hydrophobic solvent; and (f) from 30 to 60 wt % such as 35 to45 wt % of the HVLCM. Typically in this embodiment the HVLCM is SAIB;the network former is selected from CAB, cellulose acetate phthalate,ethyl cellulose, hydroxypropylmethyl cellulose and cellulose triacetate;the first viscosity enhancing agent is HEC, hydroxypropylcellulose,carboxymethylcellulose, polyethylene glycol and polyvinylpyrrolidone;the hydrophilic solvent is selected from triacetin,N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate,propylene carbonate and glycofurol; and the hydrophobic solvent is IPM.Preferably, the HVLCM is SAM, the network former is CAB, the firstviscosity enhancing agent is HEC, the hydrophilic solvent is triacetin,and the hydrophobic solvent is IPM.

The controlled release system can further comprise a second viscosityenhancing agent such as silicone dioxide. The second viscosity enhancingagent is typically present in an amount from 0.1 to 6 wt % such as 1 to2 wt %.

Once all of the constituents have been selected to produce a controlledrelease carrier system in accordance with the present invention, aliquid pharmaceutical formulation can be prepared by simply mixing, forexample a HVLCM, a rheology modifier, a network former, the activeagent, a solvent and any additional additives. The formulations of thepresent invention are produced as liquid mixtures, and have a number ofexcipient ingredients that are in solution, suspension, or in partialsolution within the final formulation. Suitable methods for compoundingor manufacturing the formulations make use of typicalpharmaceutical/chemical mixing and handling apparatus and techniques.Since the liquid formulations of the invention are formed from a numberof highly viscous liquids and solids, they will tend to haveexceptionaly high final viscosities. Accordingly, the specific equipmentand techniques employed in the manufacture of such formulations arepreferably selected so as to accommodate such material demands. Inparticular, various excipients such as network formers, are typicallyadded to the formulation mixture in the solid or semi-solid state, andas such they may be screened or otherwise size-reduced prior to additionto a formulation mixing apparatus. Other solid excipients may requiremelting prior to addition to the liquid mixture. The HVLCM materials arevery high viscosity liquid materials, however they tend to exhibit adramatic reduction in viscosity with increases in heat, and as such themixing apparatus may be heated to accommodate the addition of the HVLCMmaterial or other similar materials. However, the mixing and processingconditions must take into account the final integrity of the formulationand the mixing conditions are thus preferably selected so as to have alow-sheer effect on the formulation, and/or to avoid any extended orpronounced excursions into high or low heat conditions. Once theformulation has been properly combined, an appropriate amount of theresulting liquid mixture can be placed into a suitable capsule, such asa gelatin capsule or the like to provide an oral pharmaceutical dosageform. Alternative liquid formulations may include emulsifying themixture in water, and introducing this emulsion into a capsule.

With regard to a formulation that is formed from the mixture of apharmacologically active agent, a HVLCM, a network former, a rheologymodifier, a hydrophilic agent and a solvent, one suitable manufacturingor compounding process includes the steps of: (i) preheating the HVLCM;(ii) mixing the solvent with the preheated HVLCM to form a uniformsolution of the HVLCM in the solvent; (iii) dispersing the networkformer in the solution to dissolve the network former in the solution;mixing from 5 to 30%, for example 10 to 20%, of the rheology modifieror, optionally, a solution of a stabilising agent and from 5 to 30%, forexample 10 to 20%, of the rheology modifier with the formulation; (iv)adding and mixing the pharmacologically active agent;

adding and mixing the hydrophilic agent; (v) optionally, adding andmixing a viscosity enhancing agent; and (vi) adding and mixing thebalance of the rheology modifier. The process may further include thestep of filling capsules with the formulation thus obtained and,optionally, packaging the filled capsules into unit dose blisters ormultidose plastic bottles.

Step (i) is carried out to reduce the viscosity of the HVLCM so that itreadily flows and other components can be easily mixed into it. Step (i)may be carried out at, for example, from 50 to 65° C. or 50 to 60° C. or55 to 65°. Typically, steps (ii) to (vi) are each carried out at such atemperature.

With regard to a formulation that is formed from the mixture of apharmacologically active agent, a HVLCM, a network former, a rheologymodifier, a hydrophilic agent and a solvent, a suitable manufacturing orcompounding process may include the steps of: (i) preheating the HVLCM;(ii) mixing the solvent with the preheated HVLCM to form a uniformsolution of the HVLCM in the solvent; (iii) optionally, mixing asolution of a stabilising agent and from 5 to 30%, for example 10 to20%, of the rheology modifier with the solution obtained in precedingstep; (iv) adding and mixing the rheology modifier or, if step (iii) iseffected, the balance of the rheology modifier with the solutionobtained in step (ii) or (iii); (v) optionally, adding and mixing aviscosity enhancing agent with the formulation obtained in the precedingstep; (vi) adding and dispersing the network former into the solutionobtained in step (iv) or, if step (v) is effected, step (v) therebydissolving the network former in the solution; (vii) adding and mixingthe pharmacologically active agent with the formulation obtained in theprevious step; and (viii) adding and mixing the hydrophilic agent withthe formulation obtained in step (vii).

Furthermore, the process can further include the step of fillingcapsules with the formulation thus obtained and, optionally, packagingthe filled capsules into unit dose blisters or multidose plasticbottles.

Again, step (i) is carried out to reduce the viscosity of the HVLCM sothat it readily flows and other components can be easily mixed into it.Step (i) may be carried out at, for example, from 50 to 65° C. or 50 to60° C. or 55 to 65°. Typically, steps (ii) to (viii) are each carriedout at such a temperature. In this process, though, lower temperaturescan be maintained in steps (ii) to (viii). Each of these steps maytherefore be conducted at, for example, 35 to 65° C. such as 35 to 60°C. or 40 to 60°.

With regard to a formulation that is formed from the mixture of apharmacologically active agent, a HVLCM, a network former, a firstviscosity enhancing agent, a hydrophilic solvent and a hydrophobicsolvent, a suitable manufacturing or compounding process may include thesteps of: (i) preheating the HVLCM;

mixing the hydrophilic solvent with the preheated HVLCM to form auniform solution of the HVLCM in the solvent; (ii) dispersing thenetwork former in the solution to dissolve the network former in thesolution; (iii) mixing from 5 to 30%, for example from 10 to 20%, of thehydrophobic solvent or, optionally, a solution of a stabilising agentand from 5 to 30%, for example from 10 to 20%, of the hydrophobicsolvent with the formulation; (iv) adding and mixing thepharmacologically active agent; (v) adding and mixing the firstviscosity enhancing agent; (vi) optionally, adding and mixing a secondviscosity enhancing agent; and (vii) adding and mixing the balance ofthe hydrophobic solvent.

Furthermore, the process can further include the step of fillingcapsules with the formulation thus obtained and, optionally, packagingthe filled capsules into unit dose blisters or multidose plasticbottles.

Step (i) is carried out to reduce the viscosity of the HVLCM so that itreadily flows and other components can be easily mixed into it. Step (i)may be carried out at, for example, from 50 to 65° C. or 50 to 60° C. or55 to 65°. Typically, steps (ii) to (viii) are each carried out at sucha temperature.

Also with regard to a formulation that is formed from the mixture of apharmacologically active agent, a HVLCM, a network former, a firstviscosity enhancing agent, a hydrophilic solvent and a hydrophobicsolvent, a suitable manufacturing or compounding process may include thesteps of: (i) preheating the HVLCM; (ii) mixing the hydrophilic solventwith the preheated HVLCM to form a uniform solution of the HVLCM in thesolvent; (iii) optionally, mixing a solution of a stabilising agent andfrom 5 to 30%, for example 10 to 20%, of the hydrophobic solvent withthe solution obtained in preceding step; (iv) adding and mixing thehydrophobic solvent or, if step (iii) is effected, the balance of thehydrophobic solvent with the solution obtained in step (ii) or (iii);(v) optionally, adding and mixing a second viscosity enhancing agentwith the formulation obtained in the preceding step; (vi) adding anddispersing the network former into the solution obtained in step (iv)or, if step (v) is effected, step (v) thereby dissolving the networkformer in the solution; (vii) adding and mixing the pharmacologicallyactive agent with the formulation obtained in the previous step; and(viii) adding and mixing the first viscosity enhancing agent with theformulation obtained in step (vii). The process may further include thestep of filling capsules with the formulation obtained in the processand, optionally, packaging the filled capsules into unit dose blistersor multidose plastic bottles.

In this process embodiment, step (i) is carried out to reduce theviscosity of the HVLCM so that it readily flows and other components canbe easily mixed into it. Step (i) may be carried out at, for example,from 50 to 65° C. or 50 to 60° C. or 55 to 65°. Typically, steps (ii) to(viii) are each carried out at such a temperature. In this process,though, lower temperatures can be maintained in steps (ii) to (viii).Each of these steps may therefore be conducted at, for example, 35 to65° C. such as 35 to 60° C. or 40 to 60°.

With regard to a formulation that is formed from the mixture of apharmacologically active agent, a HVLCM, a network former, a rheologymodifier, a hydrophilic agent and a solvent, one suitable manufacturingor compounding process would include the steps of: preheating the HVLCM;mixing the solvent with the preheated HVLCM to form a uniform solutionof the HVLCM in the solvent; dispersing the network former in thesolution to dissolve the network former in the solution; mixing from 5to 30% of the rheology modifier or, optionally, a solution of astabilising agent and from 5 to 30% of the rheology modifier with theformulation; add and mixing the pharmacologically active agent; addingand mixing the hydrophilic agent; and, optionally, adding and mixing aviscosity enhancing agent, and adding and the balance of the rheologymodifier. Furthermore, the process can include the step of fillingcapsules with the formulation obtained in the process and, optionally,packaging the filled capsules into unit dose blisters or multidoseplastic bottles.

With regard to a formulation that is formed from the mixture of apharmacologically active agent, a HVLCM, a network former, a rheologymodifier, a hydrophilic agent and a solvent, a suitable manufacturing orcompounding process may include the steps of: preheating the HVLCM to afirst temperature range; mixing the solvent with the preheated HVLCM toform a uniform solution of the HVLCM in the solvent; optionally, mixinga solution of a stabilising agent and from 5 to 30% of the rheologymodifier with the solution obtained in preceeding step at a temperaturein a second range; adding and mixing the rheology modifier or, if stepthe balance of the rheology modifier with the solution obtained in theearlier step whilst maintaining the temperature in the second range;optionally, adding and mixing a viscosity enhancing agent with theformulation obtained in the preceeding step whilst maintaining thetemperature in the second range; adding and dispersing the networkformer into the solution thus obtained or, whilst maintaining thetemperature of the solution in the second range, thereby dissolving thenetwork former in the solution; adding and mixing the pharmacologicallyactive agent with the formulation obtained in the previous step whilstmaintaining the temperature in the second range; adding and mixing thehydrophilic agent whilst maintaining the temperature in the secondrange. Furthermore, the process can include the step of filling capsuleswith the formulation obtained in the process and, optionally, packagingthe filled capsules into unit dose blisters or multidose plasticbottles.

With regard to a formulation that is formed from the mixture of apharmacologically active agent, a HVLCM, a network former, a firstviscosity enhancing agent, a hydrophilic solvent and a hydrophobicsolvent, a suitable manufacturing or compounding process may include thesteps of: preheating the HVLCM; mixing the solvent with the preheatedHVLCM to form a uniform solution of the HVLCM in the solvent; dispersingthe network former in the solution to dissolve the network former in thesolution; mixing from 5 to 30% of the rheology modifier or, optionally,a solution of a stabilising agent and from 5 to 30% of the rheologymodifier with the formulation; adding and mixing the pharmacologicallyactive agent; adding and mixing the hydrophilic agent; and, optionally,adding and mixing a viscosity enhancing agent, and adding and thebalance of the rheology modifier. Furthermore, the process can includethe step of filling capsules with the formulation obtained in theprocess and, optionally, packaging the filled capsules into unit doseblisters or multidose plastic bottles.

With regard to a formulation that is formed from the mixture of apharmacologically active agent, a HVLCM, a network former, a firstviscosity enhancing agent, a hydrophilic solvent and a hydrophobicsolvent, a suitable manufacturing or compounding process may include thesteps of: preheating the HVLCM to a first temperature range; mixing thesolvent with the preheated HVLCM to form a uniform solution of the HVLCMin the solvent; optionally, mixing a solution of a stabilising agent andfrom 5 to 30% of the rheology modifier with the solution obtained inpreceeding step at a temperature in a second range; adding and mixingthe rheology modifier or, if step the balance of the rheology modifierwith the solution obtained in the earlier step whilst maintaining thetemperature in the second range; optionally, adding and mixing aviscosity enhancing agent with the formulation obtained in thepreceeding step whilst maintaining the temperature in the second range;adding and dispersing the network former into the solution thus obtainedor, whilst maintaining the temperature of the solution in the secondrange, thereby dissolving the network former in the solution; adding andmixing the pharmacologically active agent with the formulation obtainedin the previous step whilst maintaining the temperature in the secondrange; adding and mixing the hydrophilic agent whilst maintaining thetemperature in the second range. Furthermore, the process can includethe step of filling capsules with the formulation obtained in theprocess and, optionally, packaging the filled capsules into unit doseblisters or multidose plastic bottles.

A number of other suitable lab-scale, GMP and commercial manufacturingmethods for producing the abuse-resistant dosage forms and formulationsof the present invention are described in Examples 1 and 2 below.

In certain preferred embodiments, the oral dosage form is composed of aliquid formulation containing the active agent and the controlledrelease carrier system encapsulated within an enclosure or capsule,preferably biodegradable, such as a capsule or a gelatin capsule(“gelcap”), wherein the capsule is made of a substance that degrades orotherwise dissociates when exposed to conditions present in thegastro-intestinal tract of a mammal. Capsules and gelcaps are well knownin drug delivery technology and one of skill could select such a capsuleas appropriate for delivery of a particular active agent. Once thecapsule has dissolved or dissociated from the formulation, theformulation of the invention generally remains intact, especially forhydrophobic formulations, and passes through the GI tract withoutemulsification or fragmentation.

In certain more specific embodiments the invention encompasses an oraldosage form comprising a liquid formulation contained within abiodegradable capsule, wherein the formulation comprises an active agentand a HVLCM, and wherein the capsule is made of a substance thatdegrades when exposed to conditions present in the gastro-intestinaltract of a mammal. In certain embodiments the capsule comprises gelatinor synthetic polymers such as hydroxyl ethyl cellulose and hydroxylpropylmethyl cellulose. Gelcaps can be of the hard or soft variety,including, for example, polysaccharide or hypromellose acetate succinatebased caps (e.g., Vegicaps brand, available from Catalent). The capsulecan also be coated with an enteric coating matereial such as AQIAT(Shin-Etsu) to delay release Gelatin capsules are well suited fordelivering liquid formulations such as vitamin E and cod-liver oil.Gelatin capsules are stable in storage, but once in the acid environmentof the stomach (low pH less than about pH 4-5), the gelcap dissolvesover a 1-15 minute period.

In certain embodiments, the abuse-resistant oral pharmaceutical dosageforms may be formulated so as to produce particular controlled plasmalevels of an active agent over a particular period. This is obviously ofgreat importance in maintaining a plasma level within an appropriatetherapeutic range. An appropriate therapeutic range will vary dependingon the active agent, but can range from femtogram/mL levels up to abovemicrogram/mL levels for a desired period of time. For example, a singledose of a dosage form disclosed herein may result in maintenance ofplasma levels of greater than 5 ng/mL for a period of greater than 8hours. In other embodiments, the plasma level achieved using a singledose may be greater than 5 ng/mL for a period of greater than 10 hours,greater than 12 hours, greater than 14 hours, greater than 16 hours,greater than 18 hours, or greater than 20 hours. In yet otherembodiments, the plasma level achieved using a single dose may begreater than 5 ng/mL, greater than 10 ng/mL, greater than 15 ng/mL,greater than 20 ng/mL, greater than 30 ng/mL, greater than 40 ng/mL, orgreater than 50 ng/mL for a period of 4, 8, 10, 12, 14, 16, 18, 20 or 24hours. The maximum plasma concentration of an active agent may bereached at a time following administration from between 0.1 hr to about24 hr, or from about 0.25 hr to 10 hr, or from about 0.25 hr to 8 hr, orfrom about 0.5 hr to 6 hr, or from about 0.5 hr to 4 hr, or from about0.5 hr to 2 hr, or from about 0.5 hr to 1 hr. The time to maximum plasmaconcentration may be adjusted by adjusting various components of thecontrolled release carrier system as taught herein.

The plasma levels obtained may be adjusted by adjusting the dose of theactive agent, and/or by adjusting the formulation and other componentsof the controlled release carrier system, and desirable plasma levelswill depend on the therapeutic range or its index for any particularactive agent. It is readily within the skill of one in the art todetermine the desired therapeutic index.

The rate of active agent release from the dosage form may be varieddepending on the agent used and the dosage required. Release rates maybe different in different parts of the GI tract, and release rates maybe averaged over the time of transit through the GI tract (approximately8-24 hrs). Typical average release rates may vary substantially. Formany active agents, they may range from about 0.01 to 500 mg/hr, from0.5 to 250 mg/hr, 0.75 to 100 mg/hr, 1.0 to 100 mg/hr, 2.0 to 100 mg/hr,5 to 100 mg/hr, 10 to 100 mg/hr, 10 to 80 mg/hr, 20 to 50 mg/hr, orabout 20 to 40 mg/hr.

Dosage regimens for a particular active agent of interest may bedetermined by the physician in accordance with standard practices. Onceper day (QD) or twice per day (BID) dosing may be used to maintain asufficient clinical effect, e.g., to maintain pain relief.

EXAMPLES

Please note that the examples described herein are illustrative only andin no way limit the scope of the invention.

Example 1 Preparation of Formulations

(Lab-Scale Manufacturing Processes)

Three different lab-scale manufacturing processes for the dosage formsof the present invention were developed and carried out as follows. Thefollowing raw materials were used to create formulations used in theprocesses: Oxycodone HCl, micronized (“OXY”); Isopropyl Myristate, NF(“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”);Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF(“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAM”);Triacetin USP (“TA”); Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”); Sodium Lauryl Sulfate NF(“SDS”); and Labrafil M2125 CS (“LAB”). The specific details for thefive different formulations produced using the three lab-scalemanufacturing processes of this Example 1 are disclosed below inTable 1. The batch size for the various formulations ranged between 900g and 1 kg.

TABLE 1 Process OXY SAIB TA CAB IPM EC SiO₂ BHT SDS LAB No. Scheme (wt%) (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) 1 1,2, 3 7.27 39.96 29.64 4.64 13.91 5.56 1.85 0.02 1.4 — 2 1, 2, 3 7.2738.38 25.59 4.64 13.91 5.56 1.85 0.02 — 2.78 3 2 7.27 37.27 27.61 5.5614.84 5.56 1.85 0.02 — — 4 2 7.27 37.54 27.81 5.1 14.84 5.56 1.85 0.02 —— 5 2 7.27 36.64 30.33 5.56 12.98 5.56 1.85 0.02 — —

The primary mixing apparatus used in each of the lab-scale manufacturingprocesses was a Ross Model No. HSM 100 LCI, equipped with propeller typeimpeller (4 blade) with a diameter of 2.25 inches. The mixing containerthat was used was a 2 liter Glass Jar with an internal Diameter (mixingarea) of 4.181 inches. A Silverson Mixer (Model No. L4RT) was used ineach process for homogenization after addition of the SiO₂, wherehomogenization was carried out for 10 minutes, and the rotor speed waskept at 6000 rpm. During the homogenization process, the temperature ofthe bulk materials was constantly monitored and was kept below 75° C.During each of the other steps of the manufacturing processes, the bulktemperature was maintained around 60° C. throughout using a water bath,and the mixing speed for the mixing apparatus was kept constant at 1500rpm throughout (with the exception that during addition of any solidmaterials, mixing speed was increased for a short time to create anefficient vortex to disperse the solid material within the bulkmaterial). Mixing times were kept at 30 minutes after addition of eachmaterial except after addition of CAB. In each process, it took about 2hours for the CAB material to go into solution. After each manufacturingprocess was completed, the resulting formulations were reheated andinjected into soft gel caps using a standard needle and syringe toprovide 10 mg and 40 mg oxycodone gel cap dosage forms.

All of the raw materials were used as obtained from the variousmanufactures with the following exceptions. The active agent (oxycodoneHCL) raw material was found to have a variety of different particlesizes and was further subject to agglomeration upon standing at ambientconditions. Accordingly, the oxycodone material was subjected to a jetmilling process in order to micronize the solid material into asubstantially homogenous particle size. The jet mill apparatus was aModel No. 00 Jet-O-Mizer Jetmill (Fluid Energy). The processingconditions used to process batch sizes of around 80 g, were as follows:nitrogen gas (N₂) was used instead of compressed air, with the pushernozzle set at 100 psi, and the grinding nozzles (Nozzle #1 and #2) setat 90 psi. Processing time was around 2 hours. After collection from thejet mill apparatus, the micronized oxycodone was passed through a20-mesh stainless steel screen and weighed. This micronization processwas carried out just prior to each manufacturing process in order toavoid any possible agglomeration of the processed material. The CAB rawmaterial was washed using ethanol (EtOH) and then dried to removepossible contaminants.

In the first lab-scale manufacturing process (Process Scheme 1), theorder of addition of the various material constituents was adjusted suchthat the active agent (oxycodone) was added at the end of the process.In earlier lab scale processes, the CAB/triacetin solution was added tocarrier material SAIB at beginning of the process. In this ProcessScheme 1, the CAB material was dispersed in the SAIB material at thebeginning of the process, prior to addition of the triacetin. The flowchart for Process Scheme 1 is depicted in FIG. 1A. Process temperatureswere maintained at 60° C.±5° C. throughout the process run. CABdissolution after addition of the triacetin took approximately 2 hoursand was confirmed by visual observation of a clear thick liquid that wasfree from any solid aggregates. About 15% of the IPM was added with theBHT and SDS (where used), with the balance being added as a rinse. Inaddition, the homogenizer was used for 10 minutes after addition of theSiO₂ into the vortex created by the impeller.

In the second lab-scale manufacturing process (Process Scheme 2), theoxycodone active agent was added prior to addition of the HEC and SiO₂materials. The flow chart for Process Scheme 2 is depicted in FIG. 1B.Here again, process temperatures were maintained at 60° C.±5° C.throughout the process run. CAB dissolution took approximately 2 hoursand was confirmed by visual observation of a clear thick liquid that wasfree from any solid aggregates, and about 15% of the IPM was added withthe BHT and SDS (where used), with the balance being added as a rinse.In addition, the homogenizer was used for 10 minutes after addition ofthe SiO₂ into the vortex created by the impeller.

In the third lab-scale manufacturing process (Process Scheme 3), theprocess was developed such that viscosity of the formulation is rampedup (from low to high viscosity, low shear mixing method) duringsuccessive steps of the process to provide for a low-shear process thatwould be suitable for manufacturing scale-up. In addition, the oxycodoneactive agent was dispersed in the formulation prior to addition of theCAB and HEC materials. The flow chart for Process Scheme 3 is depictedin FIG. 1C. Process temperatures were maintained at 60° C.±5° C.throughout the process run; however, unlike Process Schemes 1 and 2, thecomplete CAB component was added much later in the process, immediatelyprior to final addition of HEC. After addition of the HEC material,mixing was continued until the CAB material went into solution (toprovide a clear thick liquid that was free from any solid aggregates, asconfirmed by visual observation) which took about 2 hours. In addition,the homogenizer was used for 10 minutes after addition of the SiO₂ intothe vortex created by the impeller.

After manufacture of the various formulations using the above-describedlab-scale manufacturing processes, product performance of the dosageforms was assessed to determine if the sequence of addition of the rawmaterials had any impact on the controlled release (dissolution) andabuse-resistant (extraction) properties of dosage forms. In addition,viscosity measurements for the formulations were taken at a range oftemperatures (25, 37 and 60° C.) using a standard Brookfield viscometer(Digital Rheometer Model Nos. JPII, Model HBDV-III+CP withProgrammable/Digital Controller Model 9112; or JPI, Model LVDV-III+CP,Immersion Circulator Model 1122S LV DV III, both with CPE Spindle 52) toassess whether or not there was an appreciable difference in theresultant viscosities of formulations produced using the low shear(Process Scheme 3) method relative to the higher shear methods. As aresult of this initial viscosity assessment, it was found that thelow-shear (Process Scheme 3) manufacturing method produced formulationsthat had approximately 2 times greater viscosity than those sameformulations produced using the high-shear methods. This two-foldviscosity difference was found throughout the temperature range that wastested, suggesting that the low-shear method can produce formulationshaving a significantly higher final viscosity.

The controlled release performance of the various formulationsmanufactured in this Example 1 was tested using the in vitro dissolutiontechnique described herein below in Example 3. The abuse-resistanceperformance of the various formulations manufactured in this Example 1was tested using the in vitro alcohol extraction technique describedherein below in Example 4. With regard to the controlled releaseperformance testing, it was found that the formulation containing SDS(Formulation No. 1) had a slower cumulative release profile (reducedcontrolled release performance) when manufactured using Process Scheme1, compared with the same formulations that were manufactured usingeither Process Scheme 2 or 3. From these observations, it is possiblethat a change in the sequence of addition of the raw materials may havean effect upon release kinetics in formulations containing the SDSingredient (in Process Scheme 1, the oxycodone is added at the very laststep, whereas in Process Schemes 2 and 3, it is added much earlier inthe process). However, this difference in controlled release performancewas not noted in the formulations that do not contain the SDS ingredient(Formulation Nos. 2-5). The formulation containing LAB (Formulation No.2), and the remaining formulations without both SDS and LAB (FormulationNos. 3-5) showed no substantial difference in controlled releaseperformance regardless of the manufacturing process that was used toproduce the subject formulations.

With regard to abuse-resistance performance, the formulation thatincludes SDS (Formulation No. 1), showed an improved abuse resistanceperformance between formulation prepared using Process Scheme 1 whencompared with formulation prepared using Process Scheme 2, againsuggesting a possible sequence of addition effect that could beconsistent with the reduction in controlled release performance as notedabove. There was no substantial difference observed in the abuseresistance performance for the other formulations (Formulation Nos. 2-5)regardless of manufacturing process.

Example 1a

A GMP manufacturing process for the dosage forms of the presentinvention was developed and carried out as follows. The following rawmaterials were used to create the formulations: d-Amphetamine Sulfate(Cambrex) (“AMP”); Isopropyl Myristate, NF (“IPM”); Colloidal silicondioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF(“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate(Eastman Chemicals), (“SAM”); Triacetin USP (“TA”); Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”);Caprylocaproyl Polyoxyglycerides (Gattefosse) (“CPG”); Gelucire 50/13(Gattefosse) (“GEL”); and Polyethylene Glycol 8000 (Dow Chemical) (“PEG8000”). The specific details for the three different formulationsproduced using the GMP manufacturing processes of this Example 1a aredisclosed below in Table 2a. The batch sizes were up to 500 g.

TABLE 2a PEG AMP SAIB TA BHT CAB IPM HEC SiO₂ CPG GEL 8000 No. (wt %)(wt %) (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) (wt %) 15.45 35.16 26.04 0.02 4.96 16.07 5.67 1.89 — 4.73 — 2 7.50 36.52 27.050.02 4.86 15.73 5.55 1.85 0.93 — — 3 5.45 36.24 26.85 0.02 4.96 16.075.67 1.89 — — 2.84

The primary mixing apparatus used in the GMP manufacturing process was aRoss Model No. HSM 100 LCI, equipped with propeller type impeller (4blade) with a diameter of 2.25 inches. The mixing container that wasused was a 2 liter Glass Jar with an internal Diameter (mixing area) of4.181 inches. Temperature control was carried out using a VWR immersioncirculator and a VWR gravity convection oven model 1320. A micro mixerhomogenizing assembly for the Ross mixer was used for the finalhomogenization step. After the final mixing step, bulk formulations wereallowed to cool to room temperature for a minimum of 16 hours(overnight) prior to filling into capsules. The flow chart for theinstant GMP manufacturing process (Process Scheme 6) is depicted in FIG.1D. The specific process conditions used for Formulations 1-3 are asfollows.

For Formula 1, the final homogenization was carried out at 4000 rpm for5 minutes. The final product temperature was 51.3° C.

(Formula 1) SAIB TA BHT CAB IPM GEL AMP HEC SiO₂ Mixing speed — 500 500800-1200 1200 1200 1200-1500 1750 1880-2000 (rpm) Mixing time — 11 20 9130 39 34 35 30 (min) Formula temp. — 62.3 66.7 68.4 68 62.5 — — 69.5 (°C.) Bath temp. — 65.3 68.1 70.0 70.0 68.2 70.0 70.0 70.0 (° C.)

For Formula 2, the homogenization was carried out at 4000 rpm for 10minutes. The initial product temperature was 69.1° C., and the finalproduct temperature was 63.6° C.

(Formula 2) SAIB TA BHT CAB IPM CPG AMP HEC SiO₂ Mixing speed (rpm) —500 500 1000-1250 1250 1400 2000 2150 1400 Mixing time (min) — 11 22 8532 39 34 41 30 Formula temp. (° C.) — 68.8 69.5 70.3 68.5 70.1 — — 72.5Bath temp. (° C.) — 70.0 70.0 70.0 70.0 70.0 70.0 70.0 70.0

For Formula 3, the final homogenization was carried out at 4000 rpm for10 minutes. The initial product temperature was 71.5° C., and the finalproduct temperature was 63.1° C.

PEG (Formula 3) SAIB TA BHT CAB IPM 8000 AMP HEC SiO₂ Mixing speed — 500500 800-1200 1250 1400 1400-1600 1600 1200 (rpm) Mixing time — 11 19 10239 49 34 43 30 (min) Formula temp. — 68.8 69.5 70.3 68.5 70.1 — — 72.5(° C.) Bath temp. — 70.0 70.0 70.0 70.0 70.0 70.0 70.0 70.0 (° C.)

Example 1b

A GMP manufacturing process for the dosage forms of the presentinvention was developed and carried out as follows. The flow chart forthe instant GMP manufacturing process (Process Scheme 7) is depicted inFIG. 1E. Process temperatures were maintained at 55 to 70° C. throughoutthe process run. Mixing of the IPM/BHT mixture into the compoundingmixture was carried out with a 4 inch impeller at 1,500 rpm for 15minutes. The SiO₂ induction step was carried out an additional 2 minutesusing a rotor stator at 3,000 rpm. The homogenization step was carriedout with a 2.5 inch rotor and slotted stator for 40 minutes afteraddition of the SiO₂. The abuse-resistant oxycodone oral dosage formsused in this Example 1b were prepared using the following raw materials:Oxycodone base, micronized (“OXY”); Isopropyl Myristate, NF (“IPM”);Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylatedhydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”);Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAM”); Triacetin USP(“TA”); Sodium Lauryl Sulfate (“SLS”); Labrafil M2125 CS (“LAB”);Gelucire 44/14 (Gattefosse) (“GEL”); and Cellulose Acetate Butyrate,grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”). Theformulations were then filled into size #00 hard gelatin cap shells toproduce 80 mg dosage forms that were used as Test Capsules. The detailsof the formulations and the dosage forms containing the formulations ofthis Example 1b are disclosed below in Table 2b.

TABLE 2b OXY SAIB TA CAB IPM HEC SiO₂ BHT SLS LAB GEL (Total) OXY1 80.0281.4 208.4 42.0 112.0 42.0 14.0 0.2 — — — 780 (mg) 10.26 36.08 26.725.38 14.36 5.38 1.79 0.02 — — — (wt %) OXY2 80.0 297.5 198.4 42.0 105.042.0 14.0 0.2 1.0 — — 780 (mg) 10.26 38.14 25.43 5.38 13.46 5.38 1.790.02 0.13 — — (wt %) OXY3 80.0 285.5 190.3 42.0 105.0 42.0 14.0 0.2 —21.0 — 780 (mg) 10.26 36.60 24.40 5.38 13.46 5.38 1.79 0.02 — 2.69 — (wt%) OXY4 80.0 280.4 207.7 36.7 119.0 42.0 14.0 0.2 — — — 780 (mg) 10.2635.95 26.63 4.71 15.26 5.38 1.79 0.02 — — — (wt %) OXY5 80.0 281.0 200.842.0 119.0 42.0 14.0 0.2 1.0 — — 780 (mg) 10.26 36.03 25.74 5.38 15.265.38 1.79 0.02 0.13 — — (wt %) OXY6 80.0 286.6 191.0 36.7 112.0 42.014.0 0.2 — 17.5 — 780 (mg) 10.26 36.74 24.49 4.71 14.36 5.38 1.79 0.02 —2.24 — (wt %) OXY7 80.0 284.4 210.7 42.0 112.0 21.0 15.8 0.2 — — 14.0780 (mg) 10.26 36.46 27.01 5.38 14.36 2.69 2.02 0.02 — — 1.79 (wt %)OXY8 80.0 282.4 209.2 38.5 112.0 42.0 15.8 0.2 — — — 780 (mg) 10.2636.21 26.82 4.94 14.36 5.38 2.02 0.02 — — — (wt %) OXY9 80.0 285.9 204.338.5 112.0 42.0 15.8 0.2 1.4 — — 780 (mg) 10.26 36.66 26.19 4.94 14.365.38 2.02 0.02 0.18 — — (wt %)

Example 1c

A GMP manufacturing process for the dosage forms of the presentinvention was developed and carried out as follows. The following rawmaterials were used to create the formulations: Hydromorphone HCl(“HMH”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); Labrafil M2125 CS (“LAB”);and Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (EastmanChemicals) (“CAB”). The formulations were filled into either size #1(HMH1) or #2 (HMH2-4) gel cap shells. The specific details for the threedifferent formulations produced using the GMP manufacturing processes ofthis Example 1c are disclosed below in Table 2c. The batch sizes were upto 500 g.

TABLE 2c Formula # HMH SAIB TA CAB IPM HEC SiO₂ BHT LAB Total HMH1 16.0108.6 80.4 15.5 41.4 7.8 5.2 0.1 — 275.0 (mg) 5.82 39.49 29.5 5.65 15.075.65 1.88 0.02 — (wt %) HMH2 16.0 104.1 77.1 15.5 41.4 15.5 5.2 0.1 —275.0 (mg) 5.82 37.86 28.05 5.65 15.07 5.65 1.88 0.02 — (wt %) HMH3 16.0101.1 74.9 15.5 38.9 15.5 5.2 0.1 7.8 275.0 (mg) 5.82 36.78 27.24 5.6514.13 5.65 1.88 0.02 2.83 (wt %) HMH4 8.0 29.8 19.9 3.6 10.8 4.3 1.4 0.12.2 80.0 (mg) 10.00 37.25 24.83 4.50 13.50 5.40 1.80 0.02 2.70 (wt %)

The flow chart for the instant GMP manufacturing process (Process Scheme8) is depicted in FIG. 1F. The process was carried out as follows. Priorto compounding, the hydromorphone active pharmaceutical ingredient (API)was milled using a Fluid Energy Jet-O-Mizer Jet mill to reduce the APIparticle size. The formulation was manufactured using a Ross HSM-100LCIoverhead mixer fitted with a 2¼ inch, 4-blade, 45° mixing blade. Thecompounding jar was held in a water bath maintained at 55-65° C.throughout the compounding cycle.

The pre-heated SAM was added to the compounding jar followed by thetriacetin solvent. The contents of the jar were mixed for a minimum of30 minutes at approximately 500 rpm. The pre-sieved network former (CAB)was slowly added to the compounding jar and mixed at 1500 to 1800 rpmuntil no granules of CAB were observed. The preservative (BHT),dissolved in a portion of the rheology modifier (IPM), was added to thecompounding jar. The remaining IPM was used to rinse the IPM/BHTcontainer and the rinse was added to the compounding jar. The contentsof the jar were mixed for a minimum of 30 minutes at approximately 1500rpm. The milled hydromorphone API was then added to the compounding jarand mixed for a minimum of 10 minutes at 2500-3500 rpm. The compoundingmass was then homogenized using a Silverson L4RT Homogenizer with asquare hole rotor stator between 5000 and 9000 rpm for 10 minutes. Thetemperature of the compounding mass was maintained below 75° C. duringthe homogenizing step. A hydrophilic agent (HEC) was then to thecompounding jar and mixed for a minimum of 30 minutes at 2500-3000 rpm.A viscosity enhancing agent (SiO₂) was then added and the mass wasallowed to mix for a minimum of 30 minutes at approximately 1500 rpm.The compounding mass was then homogenized again using a Silverson L4RTHomogenizer with a square hole rotor stator at approximately 6000 rpmfor 10 minutes. The temperature of the compounding mass was maintainedbelow 75° C. during this second homogenizing step.

The compounded mass was reheated in an oven prior to the fillingoperation. The compounded mass was filled into hard gelatin capsules andsealed using a Capsugel CFS-1000 and a 50% ethanol solution for sealing.The capsules were packaged into plastic bottles with child-resistantcaps with induction-sealed liners.

Example 1d

A GMP manufacturing process for the dosage forms of the presentinvention was developed and carried out as follows. The following rawmaterials were used to create the formulations: Hydrocodone Bitartrate(“HCB”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); Gelucire 44/14 (Gattefosse)(“GEL”); and Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed(Eastman Chemicals) (“CAB”). The formulations were filled into size #3gel cap shells. The specific details for the two different formulationsproduced using the GMP manufacturing processes of this Example 1d aredisclosed below in Table 2d. The batch sizes were up to 500 g.

TABLE 2d Formula HCB SAIB TA CAB IPM HEC SiO₂ BHT GEL Total # (mg) (mg)(mg) (mg) (mg) (mg) (mg) (02 mg) (mg) (mg) HCB1 15.0 41.8 27.8 5.2 14.242.8 1.9 0.1 1.1 110.0 (mg) 13.64 37.97 25.31 4.75 12.95 2.59 1.73 0.021.04 (wt %) HCB2 75.0 208.8 139.2 26.1 71.2 14.2 9.5 0.11 5.7 550.0 (mg)13.63 37.96 25.31 4.75 12.95 2.58 1.73 0.02 1.04 (wt %)

The flow chart for the instant GMP manufacturing process (Process Scheme9) is depicted in FIG. 1G. The process was carried out as follows.Compounding was carried out using a Ross PDM-2 mixer fitted with aplanetary paddle, side scraper, and high-speed disperser blade. The SAIBand a surfactant (Gelucire 44/14 (GEL)) were preheated in an oven at 70°C. The triacetin solvent (TA) was added to the jacketed mixing bowl andallowed to heat to the target processing temperature of 65° C. Themelted GEL was removed from the oven and dispensed into the mixing bowl.The contents were allowed to mix for 5 minutes using a planetary paddlespeed between 20 and 30 rpm. The heated SAIB was added to the mixingbowl, followed by addition of the stabilizing agent (BHT) dissolved in aportion of the IPM rheology modifier. The remaining IPM was used torinse the IPM/BHT container and the rinse was added to the mixing bowl.The contents of the bowl were mixed at a planetary paddle speed ofbetween 20 and 30 rpm and the disperser speed set between 650 and 850rpm for a minimum of 10 minutes until the mixture was visuallyhomogenous. The hydrocodone bitartrate API was added to the mixing bowland mixed using a planetary paddle speed between 20 and 30 rpm and adisperser speed between 750 and 950 rpm for a minimum of 10 minutes. Theviscosity enhancing agent (SiO₂) was added and mixed using the samemixing conditions for an additional 10 minutes.

The contents of the mixing bowl were homogenized using a Silverson L4RTHomogenizer with a square hole rotor stator at 6000 rpm for 13 to 17minutes. Following homogenization, the contents of the mixing bowl weremixed using a planetary paddle speed between 20 and 30 rpm for 30minutes under a vacuum (15 to 29 inches of mercury) to deaerate themass. After breaking the vacuum, the pre-sieved network former (CAB) wasadded to the mixing bowl followed by the pre-sieved hydrophilic agent(HEC). The compounding mass was mixed using a planetary paddle speedbetween 25 and 45 rpm and a disperser speed of 200 rpm under vacuum(15-29 inches of mercury). During this final mixing step, the compoundedmass was mixed for a minimum of 60 minutes and until no granules of CABwere observed.

The compounded mass was reheated in an oven prior to the fillingoperation. The compounded mass was filled into hard gelatin capsules andsealed using a Capsugel CFS-1000 and a 50% ethanol solution for sealing.The capsules were packaged into plastic bottles with child-resistantcaps.

Example 2 Preparation of Formulations

(Commercial-Scale Manufacturing Processes)

Two different commercial-scale manufacturing processes for the dosageforms of the present invention were developed and carried out asfollows. The following raw materials were used to create theformulations: Oxycodone base, micronized (“OXY”); Isopropyl Myristate,NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”);Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF(“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAM”);Triacetin USP (“TA”); and Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”). The specific details for theformulations produced using the commercial-scale manufacturing processesof this Example 2 are disclosed below in Table 3.

TABLE 3 OXY SAIB TA CAB IPM HEC SiO₂ BHT (wt %) (wt %) (wt %) (wt %) (wt%) (wt %) (wt %) (wt %) 5.13 40.98 27.32 4.74 14.23 5.69 1.9 0.02

All of the raw materials were used as obtained from the variousmanufactures with the following exceptions. The oxycodone base rawmaterial was found to have a variety of different particle sizes thatcould affect the final product uniformity. Accordingly, the oxycodonematerial was subjected to a jet milling process in order to micronizethe solid material into a substantially homogenous particle size. Thespecific micronization process used is described in detail below. Inaddition, the CAB raw material was washed using ethanol (EtOH) and thendried in order to remove possible contaminants.

Two different commercial-scale manufacturing processes were developedfor the dosage forms of the present invention. A schematicrepresentation of each process (hereinafter Process Scheme 4 and ProcessScheme 5, respectively) is provided in FIG. 2. In the first commercialprocess (Process Scheme 4), compounding was carried out at a 45 kgscale. In the second process (Process Scheme 5), compounding was carriedout at 150 kg scale. The same materials were used in both processes butthere were some differences in the methodology. One difference was theorder in which ingredients were added during the manufacture in order toenhance mixing and efficiency during the compounding process. Forexample, in Process Scheme 5, the IPM and SiO₂ components were addedearlier in the process and the CAB component was added later in theprocess to lower fluid viscosity during the first part of thecompounding process. Another difference in the oral dosage formsproduced by the processes was that the capsules filled from ProcessScheme 4 were not sealed, while capsules filled from Process Scheme 5were sealed using a liquid encapsulation microspray sealing (LEMS)process from Capsugel. Table 4 shows a manufacturing process andequipment comparison.

TABLE 4 Process Description Process Scheme 4 Process Scheme 5 APIMilling 8-20 kg scale 28-36 Kg scale (micronization) Spiral Jet MillSpiral Jet Mill Hosokawa Alpine model Hosokawa Alpine Model 50AS 50ASCompounding 45 kg scale 150 kg scale Multishaft mixer includingMultishaft mixer including low shear anchor agitator low shear anchoragitator high speed disperser high speed disperser high shearrotor-stator high shear rotor-stator Charles Ross mixer model CharlesRoss mixer model VMC 10 PVM 40 Encapsulation Hard gelatin capsulefilling Hard gelatin capsule filling machine machine Shionogiencapsulator Zanasi encapsulator model model F-40 40E Capsule None-capsules were not Capsules sealed with LEMS Sealing sealed technologyCapsugel sealing machine model LEMS30

Compounding for Process Scheme 4 was carried out using a Ross VMC-10Mixer with SLIM. Accordingly, all references to a specific rpm numericthroughout this compounding process correspond to this model. In a firststep, sucrose acetate isobutyrate (SAIB) was preheated to 50-65° C. andthen added into a compounding vessel with an anchor speed of at 20-40rpm. The temperature of the SAIB was maintained at 50-60° C. In a secondstep, triacetin (TA) was added into the compounding vessel and mixed atanchor speed of 20-40 rpm and a disperser speed of 700-2000 rpm. Thevessel contents were mixed to achieve a uniform solution of SAIB intriacetin. Again, the mixture temperature was maintained at 50-60° C. Ina third step, pre-sieved, cellulose acetate butyrate (CAB) was inductedinto the vessel using high shear dispersion during the addition toprevent formation of agglomerates. The vessel contents were mixed withan anchor speed of 20-50 rpm, a rotor stator speed of 700-4500 rpm and adisperser speed of 700-3500 rpm until the CAB was completely dissolvedand a clear liquid formulation was formed. After formation, the vesselcontents were mixed for an additional thirty minutes with the sameanchor, rotor stator and disperser speeds. In a fourth step, in aseparate container, a solution was prepared containing butylatedhydroxytoluene (BHT) and approximately 15% portion of isopropylmyristate (IPM). A 10% portion of the IPM may be set aside to be used asa rinse solvent later in the process. The remaining quantity of theIPM-BHT solution was subsequently added to the compounding vessel andmixed to achieve uniformity with an anchor speed of 20-50 rpm anddisperser speed of 700-3500 rpm. After formation of a uniformformulation mixture, the vessel contents were mixed for an additionalfive minutes with the same anchor and disperser speeds. During theadditional mixing, the stator was jogged as necessary at 700-1200 rpm.Again, the formulation mixture temperature was maintained at 50-60° C.In a fifth step, oxycodone (base) was inducted into the compoundingvessel and mixed to achieve uniformity with an anchor speed of 20-50rpm, disperser speed of 700-3500 rpm and a rotor stator speed of800-4500 rpm. The formulation mixture temperature was maintained at55-65° C. The vessel contents were mixed for a minimum of an additionaltwo minutes with the same anchor, disperser and rotor stator speeds. Ina sixth step, hydroxyethyl cellulose (HEC) was inducted into the vesselusing high shear dispersion during the addition and mixed to achieve auniform dispersion with an anchor speed of 20-50 rpm, disperser speed of700-3500 rpm and a rotor stator speed of 800-4500 rpm. The vesselcontents were mixed for an additional two minutes with the same anchor,disperser and rotor stator speeds. Again, the formulation mixturetemperature was maintained at 55-65° C. In a seventh step, colloidalsilicon dioxide (SiO₂) was inducted into the vessel using high sheardispersion during the addition and mixed with an anchor speed of 20-50rpm, disperser speed of 700-3500 rpm and a rotor stator speed of800-4500 rpm. The vessel contents were mixed for a minimum of anadditional two minutes with the same anchor, disperser and rotor statorspeeds. Again, the formulation mixture temperature was maintained at55-65° C. In an eighth step, IPM was inducted into the vessel and mixedwith an anchor speed of 20-50 rpm, disperser speed of 700-2000 rpm androtor stator speed of 1500-3000 rpm. The vessel contents werecontinuously mixed with anchor and maintained at 50-60° C. The finalcompounded formulation mass was de-aerated by vacuum and flushed withnitrogen at 4-5 psig for at least five minutes. The controlled-releaseformulation mass was filled into hard gelatin capsules to produceabuse-resistant oral dosage forms in accordance with the presentinvention, and then packaged into unit dose blisters or multidoseplastic bottles with child-resistant closures for clinical supply.

Compounding for Process Scheme 5 was carried out with a Ross PVM-40Mixer with SLIM. Accordingly, all references to a specific rpm numericthroughout the compounding procedure described below correspond to thismodel. In a first step, sucrose acetate isobutyrate (SAM) was preheatedto 50-65° C. and added to a compounding vessel. In a second step,triacetin was added to the compounding vessel. In a third step, abutylated hydroxytoluene/isopropyl myristate solution was prepared bydispensing a portion of isopropyl myristate (IPM) (balance of IPM isadded in next step) into a separate stainless steel container. Butylatedhydroxytoluene (BHT) was added to the container and the solution wasmixed for at least ten minutes until the BHT was dissolved. The BHT/IPMsolution was then added to the compounding vessel. In a fourth step, IPMwas added to the compounding vessel and mixed to homogeneity with ananchor speed of 10-50 rpm and a disperser speed of 1-2550 rpm. Themixture temperature was maintained at 35-50° C. In a fifth step,colloidal silicon dioxide (SiO₂) was inducted into the compoundingvessel and mixed to achieve uniform dispersion with an anchor speed of10-50 rpm (e.g., 20 rpm), a disperser speed of 1-2550 rpm (e.g., 1000rpm) and an rotor stator speed of 1-3600 rpm (e.g. 2500 rpm). Again themixture temperature was maintained at 35-50° C. The vessel contents weremixed for an additional two to four minutes with the same anchor,disperser and rotor stator speeds. In a sixth step, cellulose acetatebutyrate (CAB) was inducted into to the compounding vessel and mixedwith an anchor speed of 10-50 rpm (e.g., 20 rpm), a disperser speed of1-2550 rpm (e.g., 1500 rpm) and a rotor stator speed of 1-3600 rpm(e.g., 3000 rpm). The formulation mixture temperature was maintained at40-60° C. The vessel contents were mixed for an additional two to fourminutes with the same anchor, disperser and rotor stator speeds. In aseventh step, oxycodone (base) was inducted into the compounding vesseland mixed to achieve a uniform dispersion with an anchor speed of 10-50rpm (e.g., 20 rpm), a disperser speed of 1-2550 rpm (e.g., 1500 rpm),and an speed of 1-3600 rpm (e.g., 3000 rpm). Again the controlledrelease formulation mixture temperature was maintained at 40-60° C. Thevessel contents were mixed for an additional two to four minutes withthe same anchor, disperser and rotor stator speeds. In an eighth step,hydroxyethyl cellulose (HEC) was inducted into the compounding vesseland mixed with an anchor speed of 10-50 rpm (e.g., 20 rpm), a disperserspeed of 1-2550 rpm (e.g., 1500 rpm), and a rotor stator speed of 1-3600rpm (e.g., 3000 rpm). Again the controlled release formulation mixturetemperature was maintained at 40-60° C. The vessel contents were mixedfor an additional two to four minutes with the same anchor, disperserand rotor stator speeds. The final compounded controlled releaseformulation mass was de-aerated by vacuum at no less than 14 mm Hg forno less than two hours with anchor speed of 10-50 rpm (e.g., 20 rpm) anddispersion speed of 1-2250 rpm (e.g., 1250 rpm). The compounded,controlled release formulation mass was filled into hard gelatincapsules to produce abuse-resistant oral dosage forms in accordance withthe present invention. More particularly, the compounded, controlledrelease formulation mass was encapsulated using a Zanasi Liqui-FillEncapsulator and sealed using a LEMS30 Capsule Sealer. Initially, thecompounded mass is transferred from the Ross PVM-40 Mixer to a ZanasiHopper. The transfer lines are heated with a heated hose controller to atemperature of 55-65° C. Then, a Zansai Liqui-Fill Encapsulator wasreadied by adjusting the Stroke Scale until the proper fill weight isobtained and the temperature of the compounded mass for filling ismaintained at 60-65° C. Depending upon the size of the dosage formcapsule, a variety of filling nozzles were designed with varying nozzlediameters (e.g., 1.2-2.0 mm) for use on the Encapsulator. For a 5 mg, 10mg or 20 mg capsule dosage form, a 1.2 mm diameter nozzle is used. For a30 mg or 40 mg capsule dosage form, a 1.5 mm diameter nozzle is used.Next, the filled capsule dosage forms are removed from the ZansaiLiqui-Fill Encapsulator into a collection container and sealed using theLEMS30 Capsule Sealer (liquid encapsulation microspray sealing) fromCapsugel and packaged into unit dose blisters or multidose plasticbottles with child-resistant closures.

In some cases, the oxycodone base used in Process Scheme 4 or ProcessScheme 5 was micronized. Micronization of the oxycodone was conductedusing a Hosokawa Alpine Spiral Jet Mill. In operation, a feed materialcomprising a non-micronized opioid is injected into a flat cylindricalgrinding chamber, the chamber having nozzles arranged tangentially on aperipheral wall, in the presence of a propellant air pressure andgrinding air pressure appropriate for providing the desired flowdynamics within the chamber needed to effect collision of the opioidparticles with each other. An appropriate speed and pressure of thepropellant air pressure (such as an injector air pressure of 6.8 Bar)and the grinding air pressure (such as 6.2 Bar) is applied such that aparticle on particle collision and interaction with the chamber wallresults. The injector gas pressure was always approximately 0.3 to 0.7Bar higher than grinding pressure to obtain constant flow of oxycodoneinto the spiral jet mill. A micronized particle thus occurs, providingan opioid preparation having a reduced particle size, the particle sizebeing less than about 10 μm. The larger particles are held in the millby centrifugal (mass) force, while the fine, micronized particles leavethe mill in an air stream and are collected (drag force). One set ofprocessing parameters that may be used in the methods for preparing amicronized opioid preparation within a jet gas mill, includes, a batchsize of 4 kg; injector clearance default of +3 mm; a feed rate of 40 to50 g/min; a grinding gas pressure of 6.8 Bar and an injector gaspressure of 6.2 Bar. Immediately following micronization, the micronizedoxycodone is packaged in plastic bags with dessicant and then stored inplastic drums to preserve the integrity of the micronized particles.This is necessary to maintain stabilized micronized opioid particlepreparations. The micronized opioids, particularly the salt forms suchas oxycodone HCl or hydromorphone HCl, are hydroscopic. The immediatepackaging with dessication is required to prevent agglomeration and/orfused particles. For example, the micronized oxydocone is placed into alabeled anti-static bag and secured with a cable or twist tie at theopen end of the bag. The anti-static bag is placed into a poly bag witha layer of eight-unit, silica gel, printer, Natrasorb® S Tyvek®four-side seal bag desiccant separating the anti-static bag from thepoly bag. The label on the anti-static bag is checked to ensure that itis visible through the poly bag and the poly bag is sealed at its openend. The poly bag is placed in a HDPE (high density polyethylene) drumwith a layer of eight-unit, silica gel, printer, Natrasorb® S Tyvek®four-side seal bag desiccant separating the poly bag from the drum. Alid is placed on the open end of the drum and secured using a uniquelynumbered security locking tag through a side lever-lock (SSL). Suchdessicant packaged and stored micronized opioid preparations may be usedin the manufacturing processes, including the compounding processesdescribed herein.

Example 3 Analysis of Formulations

(In Vitro Dissolution Testing Procedures)

In order to assess the controlled release performance of the dosageforms of the present invention, two in vitro dissolution test methodswere developed as follows. The first dissolution method (Method 1) wasbased upon USP <711> Method A for delayed-release dosage forms and usesan USP dissolution apparatus Type 2 (without basket) with a two-stagemedia (an initial volume of 750 mL of 0.1N HCl acid as the dissolutionmedium, followed by adjustment to pH 6.8 by addition of 250 mL of sodiumphosphate buffer after 2 hours). The two-stage media was selected tosimulate the pH range over which a dosage form will release active agentduring transit through the GI tract. Stainless steel coiled wire type316 is used as a sinker to ensure that the dosage forms remain at thebottom of the dissolution vessel during release rate testing.

The second dissolution method (Method 2) was optimized to assess thecontrolled release performance of the controlled release dosage forms ofthe present invention having 5, 10, 20, 30 and 40 mg of the activeagent. In this regard, the unique controlled release characteristics ofthe inventive dosage forms are such that standard dissolutionmethodology and apparatus may not bear a close relationship to the rateor extent of active agent release as observed in in vivo pharmacokineticstudies. This is due in large part to the use of very hydrophobicexcipients in the inventive dosage forms (e.g., SAM and IPM), resultingin compositions that result in a controlled release mass with low waterpermeability. Accordingly, this second method represents an enhancementof the earlier method (Method 1) to provide a better reflection of invivo release. The new method uses the paddle configuration of an USPdissolution apparatus Type 2 with a stainless steel stationary basketassembly (type 316, 20-mesh basket with 20-mesh screen ceilingmodification) attached to a modified conical low-loss evaporation coveron the dissolution vessel. These changes to the traditional apparatuswere carried out in order to place the dosage form in the high shearflow zone of the USP dissolution apparatus, with an increased paddlespeed to increase medium flow within the dissolution vessel. This new,fixed high-flow zone is located just above the rotating paddle. Duringtesting, the dissolution media perfuses the stationary basket,facilitating release of the active agent from the full surface area ofthe dosage form and thus overcoming any surface boundary layerlimitations that could result from placement of the dosage form at thebottom of the dissolution vessel. A pictorial representation of themodified dissolution vessel and paddle, with the stationary basketassembly is provided as FIG. 3. In addition to the stationary basketassembly, a screen ceiling inside the mesh basket was developed toprevent the dosage forms from floating within the basket.

Suitable stationary basket assemblies are commercially available and canbe purchased from Varian as a kit. The kit contains a mesh basket (10,20 or 40 mesh), which attaches to a basket shaft. A hole in theevaporation cover of the dissolution vessel allows the basket shaft tobe secured to it. However, the evaporation covers provided with the kitare not ideal for use in an extended controlled release test. This isbecause the covers are flat and also contain a large cut out whichallows them to be easily removed from the dissolution apparatus. Overthe course of a 24-hour dissolution test, use of the covers providedwith the kit would cause significant media loss due to evaporation.Evaporative media loss would ultimately lead to higher than expectedrelease rate profiles. Previous dissolution studies with the dosageforms of the present invention have in fact given controlled releaserate profiles well in excess of 100% release. An alternative to the kitevaporation cover was therefore developed.

The dissolution profiles using 20-Mesh Basket/20-Mesh Screen Ceiling and40-Mesh Basket/without ceiling were determined to be the same. The20-Mesh Baskets were chosen in order to maximize the hydrodynamic flowof dissolution media through the basket while minimizing leakage of thedosage form from the basket. The screen ceiling is used to confine thedosage form within the basket and improve assay variability.

In addition, Method 2 uses a single-phase dissolution medium (0.1N HClwith 0.5% (w/v) sodium dodecyl sulfate (SDS). The addition of thesurfactant (SDS) to the dissolution medium improves the ability of themedium to wet the hydrophobic controlled release mass during testing.

Finally, a reverse phase HPLC method is used for determining the activeagent concentration of the dosage form samples obtained from thedissolution testing methods of this Example 3. The mobile phase for thefirst dissolution method (Method 1) is prepared in two steps while themobile phase for the second dissolution method (Method 2) is prepared inone step. A summary of the method parameters for Methods 1 and 2 isprovided below as Table 5.

TABLE 5 Test Method Method 1 Method 2 Media 750 mL 0.1N HCl (2 hours)0.1N HCl/0.5% SDS 250 mL 0.2N Na Phosphate (1000 mL) Paddle Speed 50 RPM100 RPM Bath 37° C. 37° C. Temperature Sample Coiled Sinker StationaryBasket Assembly Containment (Type 316 stainless steel) (20 Mesh withCeiling) Sample 0.25, 0.5, 1, 2, 3, 6, 0.25, 0.5, 1, 2, 3, 6, Timepoints10, 12, 18 and 24 hours 10, 12, 18 and 24 hours Mobile Phase 65% SDSBuffer/35% CAN 0.35% SDS/0.7% Acetic SDS Buffer (0.5% SDS/1% Acid/44%ACN/56% Water Acetic Acid/20% CAN) HPLC Column Waters XTerra C18, 5 μm,Waters XTerra C18, 5 μm, 4.6 × 150 mm 4.6 × 150 mm Flow Rate 1.0 mL/min1.0 mL/min Run Time 8 min 8 min UV Detection 240 nm 240 nm Injection 20μL 20 μL Volume Column 40° C. 40° C. Temperature

Example 3a

The following in vitro dissolution test was carried out to characterizethe in vitro release of abuse-resistant oxycodone oral dosage formsacross a range of strengths (10 mg, 20 mg and 40 mg strengths).

The abuse-resistant oxycodone oral dosage forms used in this Example 3awere prepared using the following raw materials: Oxycodone base,micronized (“OXY”); Isopropyl Myristate, NF (“IPM”); Colloidal silicondioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF(“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate(Eastman Chemicals), (“SAM”); Triacetin USP (“TA”); and CelluloseAcetate Butyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals)(“CAB”). The formulations were produced using the commercial-scalemanufacturing methods (Process Schemes 4 or 5 as described above) andthen filled into size #00, #1 or #2 gel cap shells to produce 10, 20 and40 mg dosage forms that were used as Test Capsules. The details of theformulations and the dosage forms containing the formulations of thisExample 3a are disclosed below in Tables 6 and 7.

TABLE 6 OXY SAIB TA CAB IPM HEC SiO₂ BHT (wt %) (wt %) (wt %) (wt %) (wt%) (wt %) (wt %) (wt %) 5.13 40.98 27.32 4.74 14.23 5.69 1.9 0.02

TABLE 7 Capsule OXY SAIB TA CAB IPM HEC SiO₂ BHT Total Size (mg) (mg)(mg) (mg) (mg) (mg) (mg) (mg) (mg) size #2 10.0 79.9 53.3 9.2 27.7 11.13.7 0.04 195.0 size #1 20.0 159.8 106.5 18.5 55.5 22.2 7.4 0.08 390.0size #00 40.0 319.6 213.1 37.0 111.0 44.4 14.8 0.16 780.0

The dissolution study was carried out using the apparatus, reagents andmethods of the Method 2 dissolution test described above, with thesingle exception that sample timepoints were at 0.5 hour, 1, 2, 3, 6,12, 18 and 24 hour. Dissolution results were obtained on the followingTest Capsules: two sets of eight 40 mg dosage forms (n=16); one set ofeight 20 mg dosage forms (n=8); and one set of eight 10 mg dosage forms(n=8). The two sets of 40 mg dosage forms were tested using twodifferent dissolution apparatus systems. The mean data from the foursets of Test Capsules are summarized below in Table 8. The releaseprofiles from the Test Capsules are depicted in FIG. 4. As can be seenby these data, the two sets of 40 mg dosage forms had comparable releaseprofiles. In addition, the 10 mg and 20 mg dosage forms exhibited fasterrelease rates when compared to the 40 mg dosage forms. These results areconsistent with the concept that relatively smaller capsules (dosageforms with larger surface to volume ratios) will generally providefaster release since the fraction of active agent at or near the dosageform surface increases with an increased surface to volume ratio.

TABLE 8 Mean Cumulative Drug Released 0.5 hr 1 hr 2 hr 3 hr 6 hr 12 hr18 hr 24 hr 40 mg Test Capsules (Apparatus 1)  8% 14% 23% 30% 46% 70%85% 94% Mean 1  1  2  3  4  5  4  3  Std Dev 40 mg Test Capsules(Apparatus 2)  9% 14% 23% 30% 47% 69% 83% 93% Mean 1  2  3  3  5  6  6 5  Std Dev 20 mg Test Capsules 14% 24% 39% 50% 76% 101%  108%  110% Mean 2  2  3  4  5  4  2  2  Std Dev 10 mg Test Capsules 16% 25% 38% 47%67% 89% 101%  107%   Mean 2  4  8  10    14    12    7  3  Std Dev

Example 3b

The following in vitro dissolution test was carried out to: (a)characterize the in vitro release of abuse-resistant oxycodone oraldosage forms across a range of strengths (5 mg, 20 mg and 40 mgstrengths) by multi-media dissolution testing; (b) demonstrate adissolution profile similarity between dosage form product lotsmanufactured at two different manufacturing sites; and (c) demonstrate adissolution profile similarity between two different dosage form productlots (5 mg and 40 mg dosage strengths) produced with different puritygrades of the active agent (oxycodone).

The abuse-resistant oxycodone oral dosage forms used in this Example 3bwere prepared using the following raw materials: Oxycodone base,micronized (“OXY”), grade 2 (specified to contain not more than 0.25%(w/w) 14-hydroxycodeinone (14-HC)) or grade 1 (specified to contain notmore than 0.001% (w/w) 14-HC), both grades obtained from Noramco, Inc(Athens Ga.); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize #00, #1 or #4 hard gelatin cap shells to produce 5, 20 and 40 mgdosage forms that were used as Test Capsules. The details of theformulations and the dosage forms containing the formulations of thisExample 3b are disclosed below in Tables 9 and 10.

TABLE 9 OXY SAIB TA CAB IPM HEC SiO₂ BHT (wt %) (wt %) (wt %) (wt %) (wt%) (wt %) (wt %) (wt %) 5.13 40.98 27.32 4.74 14.23 5.69 1.9 0.02

TABLE 10 Capsule OXY SAIB TA CAB IPM HEC SiO₂ BHT Total Size (mg) (mg)(mg) (mg) (mg) (mg) (mg) (mg) (mg) size #4 5.0 40.0 26.6 4.6 13.9 5.51.9 0.02 97.5 size #1 20.0 159.8 106.5 18.5 55.5 22.2 7.4 0.08 390.0size #00 40.0 319.6 213.1 37.0 111.0 44.4 14.8 0.16 780.0

The dissolution study was carried out using the apparatus, reagents andmethods of the Method 2 dissolution test described above, with thefollowing exceptions: the sample timepoints were at 0.5 hour, 2, 3, 6,12, 18, 24 and 48 hour. Dissolution results were obtained on thefollowing Test Capsules: (Test 1, manufacturing site 1) twelve 40 mgdosage forms (n=12); twelve 20 mg dosage forms (n=8); and twelve 5 mgdosage forms (n=12); (Test 2, manufacturing site 2) twelve 40 mg dosageforms (n=12); twelve 20 mg dosage forms (n=8); and twelve 5 mg dosageforms (n=12); and (Test 3, high purity OXY) twelve 40 mg dosage forms(n=12); and twelve 5 mg dosage forms (n=12). The mean data obtained fromTests 1-3 are summarized below in Tables 11-13. The release profilesgrouped together by common dosage strength and dissolution mediumobtained from Tests 1-3 are depicted in FIGS. 5, 6 and 7.

TABLE 11 Mean Cumulative Drug Released 0.5 hr 2 hr 3 hr 6 hr 12 hr 18 hr24 hr 48 hr Test 1: 40 mg Test Capsules (0.1N HCl) 8% 21% 27% 42% 61%73% 82% 98% Mean 1    3  4  6  8  8  8  4  Std Dev Test 1: 40 mg TestCapsules (Acetate Buffer) 9% 22% 28% 42% 59% 71% 79% 96% Mean 1    3  3 4  5  5  5  4  Std Dev Test 1: 40 mg Test Capsules (Phosphate Buffer) 8%18% 23% 33% 49% 58% 66% 86% Mean 2    3  4  5  7  7  7  6  Std Dev Test2: 40 mg Test Capsules (0.1N HCl) 8% 19% 24% 36% 55% 68% 79% 100%  Mean3    5  6  7  8  8  8  5  Std Dev Test 2: 40 mg Test Capsules (AcetateBuffer) 9% 21% 26% 38% 54% 64% 72% 90% Mean 2    4  4  4  5  5  6  4 Std Dev Test 2: 40 mg Test Capsules (Phosphate Buffer) 8% 17% 21% 31%45% 55% 63% 87% Mean 2    3  3  4  5  6  6  6  Std Dev Test 3: 40 mgTest Capsules (0.1N HCl) 8% 25% 32% 50% 71% 83% 91% 103%  Mean 2    3 4  6  6  6  5  2  Std Dev Test 3: 40 mg Test Capsules (Acetate Buffer)7% 20% 26% 40% 59% 71% 80% 97% Mean 1    2  3  4  6  6  5  3  Std DevTest 3: 40 mg Test Capsules (Phosphate Buffer) 8% 18% 23% 34% 50% 62%72% 93% Mean 2    4  5  6  7  8  8  6  Std Dev

TABLE 12 Mean Cumulative Drug Released 0.5 hr 2 hr 3 hr 6 hr 12 hr 18 hr24 hr 48 hr Test 1: 20 mg Test Capsules (0.1N HCl)  9% 23% 30% 46% 68%81% 89% 99% Mean 1  2  3  4  6  6  4  1  Std Dev Test 1: 20 mg TestCapsules (Acetate Buffer) 11% 27% 34% 49% 66% 76% 84% 98% Mean 1  3  4 5  5  5  5  2  Std Dev Test 1: 20 mg Test Capsules (Phosphate Buffer) 9% 21% 26% 38% 54% 67% 76% 96% Mean 1  2  3  4  5  6  7  3  Std DevTest 2: 20 mg Test Capsules (0.1N HCl) 10% 26% 33% 50% 70% 83% 92% 103% Mean 3  5  6  8  9  8  6  1  Std Dev Test 2: 20 mg Test Capsules(Acetate Buffer) 11% 27% 34% 49% 66% 77% 84% 100%  Mean 2  4  5  6  6 5  5  3  Std Dev Test 2: 20 mg Test Capsules (Phosphate Buffer) 10% 23%29% 42% 61% 73% 81% 99% Mean 2  3  4  5  6  6  5  3  Std Dev

TABLE 13 Mean Cumulative Drug Released 0.5 hr 2 hr 3 hr 6 hr 12 hr 18 hr24 hr 48 hr Test 1: 5 mg Test Capsules (0.1N HCl) 17% 34% 41% 57% 81%93% 97% 99% Mean 2  4  4  6  7  3  2  2  Std Dev Test 1: 5 mg TestCapsules (Acetate Buffer) 19% 38% 46% 60% 76% 86% 91% 97% Mean 2  6  7 8  8  5  3  2  Std Dev Test 1: 5 mg Test Capsules (Phosphate Buffer) 21%38% 45% 58% 77% 89% 95% 103%  Mean 2  5  6  8  11    10    7  3  Std DevTest 2: 5 mg Test Capsules (0.1N HCl) 16% 35% 44% 61% 85% 96% 99% 102% Mean 3  6  7  9  8  4  4  4  Std Dev Test 2: 5 mg Test Capsules (AcetateBuffer) 18% 35% 42% 59% 75% 86% 92% 98% Mean 3  5  6  6  7  5  4  4  StdDev Test 2: 5 mg Test Capsules (Phosphate Buffer) 18% 35% 42% 56% 73%85% 93% 101%  Mean 3  5  6  8  9  8  6  4  Std Dev Test 3: 5 mg TestCapsules (0.1N HCl) 19% 42% 52% 74% 95% 102%  104%  106%  Mean 5  7  8 7  6  3  3  3  Std Dev Test 3: 5 mg Test Capsules (Acetate Buffer) 19%39% 47% 63% 81% 91% 96% 101%  Mean 3  4  5  7  7  4  2  2  Std Dev Test3: 5 mg Test Capsules (Phosphate Buffer) 18% 36% 43% 58% 77% 89% 97%104%  Mean 3  6  7  9  9  7  4  3  Std Dev

As can be seen by these results, Test Capsules produced at threedifferent active agent strengths (5 mg, 20 mg and 40 mg), andmanufactured at two different scales and at two different sitesdemonstrate equivalent dissolution performance in three differentaqueous buffer systems (pH 1, 4.5 and 6.8). In addition, Test Capsulesproduced at two different active agent strengths (5 mg and 40 mg) andusing two different grades of the active agent demonstrated equivalentdissolution performance in the same buffer systems. Furthermore,cumulative release rates for a Test Capsule strengths and dissolutionmedium were generally highest in 0.1N HCl, slightly slower in acetatebuffer, and slowest in phosphate buffer. This release performance wasattributed to the relatively lower solubility of the active agent(oxycodone base) at pH 6.8 (the pK_(a) of oxycodone base is 8.65).

Example 3c

The following in vitro dissolution test was carried out to characterizethe in vitro release of abuse-resistant oxycodone oral dosage formsacross a range of formulations. The abuse-resistant oxycodone oraldosage forms used in this Example 3c were prepared using the followingraw materials: Oxycodone base, micronized (“OXY”); Isopropyl Myristate,NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”);Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF(“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAM”);Triacetin USP (“TA”); Sodium Lauryl Sulfate (“SLS”); Labrafil M2125 CS(“LAB”); Gelucire 44/14 (Gattefosse) (“GEL”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize #00hard gelatin cap shells to produce 80 mg dosage forms that wereused as Test Capsules. The details of the formulations and the dosageforms containing the formulations of this Example 3c are disclosed belowin Table 14.

TABLE 14 OXY SAIB TA CAB IPM HEC SiO₂ BHT SLS LAB GEL (Total) OXY1 80.0281.4 208.4 42.0 112.0 42.0 14.0 0.2 — — — 780 (mg) 10.26 36.08 26.725.38 14.36 5.38 1.79 0.02 — — — (wt %) OXY2 80.0 297.5 198.4 42.0 105.042.0 14.0 0.2 1.0 — — 780 (mg) 10.26 38.14 25.43 5.38 13.46 5.38 1.790.02 0.13 — — (wt %) OXY3 80.0 285.5 190.3 42.0 105.0 42.0 14.0 0.2 —21.0 — 780 (mg) 10.26 36.60 24.40 5.38 13.46 5.38 1.79 0.02 — 2.69 — (wt%) OXY4 80.0 280.4 207.7 36.7 119.0 42.0 14.0 0.2 — — — 780 (mg) 10.2635.95 26.63 4.71 15.26 5.38 1.79 0.02 — — — (wt %) OXY5 80.0 281.0 200.842.0 119.0 42.0 14.0 0.2 1.0 — — 780 (mg) 10.26 36.03 25.74 5.38 15.265.38 1.79 0.02 0.13 — — (wt %) OXY6 80.0 286.6 191.0 36.7 112.0 42.014.0 0.2 — 17.5 — 780 (mg) 10.26 36.74 24.49 4.71 14.36 5.38 1.79 0.02 —2.24 — (wt %) OXY7 80.0 284.4 210.7 42.0 112.0 21.0 15.8 0.2 — — 14.0780 (mg) 10.26 36.46 27.01 5.38 14.36 2.69 2.02 0.02 — — 1.79 (wt %)OXY8 80.0 282.4 209.2 38.5 112.0 42.0 15.8 0.2 — — — 780 (mg) 10.2636.21 26.82 4.94 14.36 5.38 2.02 0.02 — — — (wt %) OXY9 80.0 285.9 204.338.5 112.0 42.0 15.8 0.2 1.4 — — 780 (mg) 10.26 36.66 26.19 4.94 14.365.38 2.02 0.02 0.18 — — (wt %)

The dissolution study was carried out using the apparatus, reagents andmethods of the Method 2 dissolution test described above, with thefollowing exceptions: sample timepoints were at 0.5 hour, 1, 2, 3, 6,10, 12, 18 and 24 hour. Dissolution results were obtained on thefollowing Test Capsules: six (n=6) each of formulations OXY1-OXY9.

The mean dissolution data from the nine sets of Test Capsules aresummarized below in Table 15.

TABLE 15 Mean Cumulative Drug Released 0.5 hr 1 hr 2 hr 3 hr 6 hr 10 hr12 hr 18 hr 24 hr Formulation # OXY1 7% 12% 20% 27% 45% 62% 69% 83% 91%Mean 1 2 4 4 6 5 5 4 4 Std Dev Formulation # OXY2 9% 16% 30% 40% 63% 81%86% 96% 101%  Mean 2 4 7 8 9 7 6 4 4 Std Dev Formulation # OXY3 5%  9%14% 19% 33% 49% 55% 70% 81% Mean 1 1 2 2 4 5 5 6 6 Std Dev Formulation #OXY4 6% 10% 17% 23% 39% 55% 60% 74% 82% Mean 2 3 3 4 4 5 5 4 3 Std DevFormulation # OXY5 7% 13% 24% 31% 49% 66% 72% 84% 91% Mean 1 4 8 9 10 109 6 4 Std Dev Formulation # OXY6 6% 10% 17% 22% 39% 57% 63% 79% 88% Mean2 2 4 5 9 10 10 8 6 Std Dev Formulation # OXY7 9% — 28% 37% 55% — 77%91% 98% Mean 1 — 2 2 3 — 3 2 1 Std Dev Formulation # OXY8 6% — 17% 23%39% — 63% 80% 91% Mean 2 — 3 4 6 — 7 6 4 Std Dev Formulation # OXY9 8% —26% 35% 53% — 75% 89% 97% Mean 0 — 1 1 1 — 1 0 1 Std Dev

Example 3d

The following in vitro dissolution test was carried out to characterizethe in vitro release of abuse-resistant hydromorphone oral dosage formsacross a range of strengths (8 mg and 16 mg strengths) and across arange of formulations.

The abuse-resistant hydromorphone oral dosage forms used in this Example3d were prepared using the following raw materials: Hydromorphone HCl(“HMH”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); Labrafil M2125 CS (“LAB”);and Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (EastmanChemicals) (“CAB”). The formulations were produced using the GMPmanufacturing method of Example 1d above (Process Scheme 8) and thenfilled into either size #1 (HMH1) or #2 (HMH2-4) gel cap shells toproduce 8 and 16 mg dosage forms that were used as Test Capsules. Thedetails of the formulations and the dosage forms containing theformulations of this Example 3d are disclosed below in Table 16.

TABLE 16 Formula # HMH SAIB TA CAB IPM HEC SiO₂ BHT LAB Total HMH1 16.0108.6 80.4 15.5 41.4 7.8 5.2 0.1 — 275.0 (mg) 5.82 39.49 29.5 5.65 15.075.65 1.88 0.02 — (wt %) HMH2 16.0 104.1 77.1 15.5 41.4 15.5 5.2 0.1 —275.0 (mg) 5.82 37.86 28.05 5.65 15.07 5.65 1.88 0.02 — (wt %) HMH3 16.0101.1 74.9 15.5 38.9 15.5 5.2 0.1 7.8 275.0 (mg) 5.82 36.78 27.24 5.6514.13 5.65 1.88 0.02 2.83 (wt %) HMH4 8.0 29.8 19.9 3.6 10.8 4.3 1.4 0.12.2 80.0 (mg) 10.00 37.25 24.83 4.50 13.50 5.40 1.80 0.02 2.70 (wt %)

The dissolution study was carried out using the apparatus, reagents andmethods of the Method 2 dissolution test described above, with thefollowing exceptions: sample timepoints were at 0.5 hour, 1, 2, 3, 6,10, 12, 18 and 24 hour. Dissolution results were obtained on thefollowing Test Capsules: six (n=6) each of formulations HMH1-HMH4.

The mean dissolution data from the four sets of Test Capsules aresummarized below in Table 17. The dissolution release profiles of twoformulations are depicted in FIG. 8.

TABLE 17 Mean Cumulative Drug Released 0.5 hr 1 hr 2 hr 3 hr 6 hr 10 hr12 hr 18 hr 24 hr Formulation # HMH1 2%  5% 10% 14% 25% 37% 42%  52% 66% Mean 1 2 3 4 6 8 8 7 7 Std Dev Formulation # HMH2 3%  6% 13% 19%35% 52% 58%  73%  84% Mean 1 1 3 4 6 7 7 7 7 Std Dev Formulation # HMH33%  6% 12% 19% 36% 54% 61%  77%  88% Mean 1 2 3 5 8 10 9 8 6 Std DevFormulation # HMH4 6% 12% 24% 36% 65% 87% 94% 101% 102% Mean 1 2 4 7 109 8 4 3 Std Dev

Example 3e

The following in vitro dissolution test was carried out to characterizethe in vitro release of abuse-resistant hydrocodone oral dosage formsacross two different formulations.

The abuse-resistant hydrocodone oral dosage forms used in this Example3e were prepared using the following raw materials: HydrocodoneBitartrate (“HCB”); Isopropyl Myristate, NF (“IPM”); Colloidal silicondioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF(“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate(Eastman Chemicals), (“SAM”); Triacetin USP (“TA”); Gelucire 44/14(Gattefosse) (“GEL”); and Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”). The formulations wereproduced using the GMP manufacturing method of Example 1e above (ProcessScheme 9) and then filled into size #3 gel cap shells to produce thedosage forms that were used as Test Capsules. The details of theformulations and the dosage forms containing the formulations of thisExample 3e are disclosed below in Table 18.

TABLE 18 Formula HCB SAIB TA CAB IPM HEC SiO₂ BHT GEL Total # (mg) (mg)(mg) (mg) (mg) (mg) (mg) (02 mg) (mg) (mg) HCB1 15.0 41.8 27.8 5.2 14.242.8 1.9 0.1 1.1 110.0 (mg) 13.64 37.97 25.31 4.75 12.95 2.59 1.73 0.021.04 (wt %) HCB2 75.0 208.8 139.2 26.1 71.2 14.2 9.5 0.11 5.7 550.0 (mg)13.63 37.96 25.31 4.75 12.95 2.58 1.73 0.02 1.04 (wt %)

The dissolution study was carried out using the apparatus, reagents andmethods of the Method 2 dissolution test described above, with thefollowing exceptions: sample timepoints were at 0.5 hour, 2, 3, 6, 12,18 and 24 hour. Dissolution results were obtained on the following TestCapsules: six (n=6) each of formulations HCB1 and HCB2. The meandissolution data from the two sets of Test Capsules are summarized belowin Table 19. The dissolution release profiles of formulations HCB1 andHCB2 are depicted in FIGS. 9A and 9B.

TABLE 19 Mean Cumulative Drug Released 0.5 hr 2 hr 3 hr 6 hr 12 hr 18 hr24 hr Formulation # HCB1 9% 28% 39% 63% 90% 100% 103% Mean 2 5 7 10 7 32 Std Dev Formulation # HCB2 5% 18% 25% 44% 67%  82%  92% Mean 1 3 4 4 43 3 Std Dev

Example 3f

The following in vitro dissolution test was carried out to characterizethe in vitro release of abuse-resistant oxymorphone oral dosage formsacross several different formulations.

The abuse-resistant oxymorphone oral dosage forms used in this Example3f were prepared using the following raw materials: oxymorphone HCl(“OMH”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); Cellulose Acetate Butyrate,grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”); andGelucire 44/14 (Gattefosse) (“GEL”). The formulations were producedusing a lab-scale manufacturing process and then filled into size #1 gelcapsules to produce the dosage forms that were used as Test Capsules.The details of the lab-scale manufacturing process are as follows. TheSAM and TA were mixed as a 1.5:1 stock solution. Temperature wasmaintained at 60° C.±5° C. throughout the process run. The SAM/TA stocksolution was mixed at 420 rpm for 15 minutes. The GEL was added andmixed into the compounding mix at 600 rpm for 15 minutes. An IPM/BHTsolution and the remaining IPM were then added, and the resultingmixture was processed at 600 rpm for 15 minutes, after which the SiO₂was added and mixed at 550 rpm for 20 minutes. Homogenization was thencarried out at 9,600 rpm for 5 minutes. Pre-screened CAB was added tothe compounding mixture, and mixed at 960 rpm for 5 minutes, thenincreased to 1,500 rpm for an additional 32 minutes to provide a placebomixture. The OMH was added to pre-heated placebo mixture (60° C.±5° C.)and combined using a spatula, followed by homogenization at 9,600 rpmfor 5 minutes to produce the final formulations. The details of theformulations and the dosage forms containing the formulations of thisExample 3f are disclosed below in Table 20.

TABLE 20 OMH SAIB TA CAB IPM HEC SiO₂ BHT GEL (Total) OMH1 40.00 226.38150.92 25.50 76.50 15.30 12.75 0.10 2.55 550 (mg) 7.27 41.16 27.44 4.6413.91 2.78 2.32 0.02 0.46 (wt %) OMH2 40.00 214.14 142.76 25.50 76.5035.70 7.65 0.10 7.65 550 (mg) 7.27 38.93 25.96 4.64 13.91 6.49 1.39 0.021.39 (wt %) OMH3 40.00 226.38 150.92 30.60 76.50 15.30 7.65 0.10 2.55550 (mg) 7.27 41.16 27.44 5.56 13.91 2.78 1.39 0.02 0.46 (wt %) OMH440.00 214.14 142.76 25.50 76.50 35.70 12.75 0.10 2.55 550 (mg) 7.2738.93 25.96 4.64 13.91 6.49 2.32 0.02 0.46 (wt %) OMH5 40.00 208.02138.68 30.60 76.50 35.70 12.75 0.10 7.65 550 (mg) 7.27 37.82 25.21 5.5613.91 6.49 2.32 0.02 1.39 (wt %) OMH6 40.00 214.14 142.76 30.60 76.5035.70 7.65 0.10 2.55 550 (mg) 7.27 38.93 25.96 5.56 13.91 6.49 1.39 0.020.46 (wt %) OMH7 40.00 220.26 146.84 30.60 76.50 15.30 12.75 0.10 7.65550 (mg) 7.27 40.05 26.70 5.56 13.91 2.78 2.32 0.02 1.39 (wt %) OMH840.00 226.38 150.92 25.50 76.50 15.30 7.65 0.10 7.65 550 (mg) 7.27 41.1627.44 4.64 13.91 2.78 1.39 0.02 1.39 (wt %) OMH9 40.00 218.73 145.8228.05 76.50 25.50 10.20 0.10 5.10 550 (mg) 7.27 39.77 26.51 5.10 13.914.64 1.85 0.02 0.93 (wt %) OMH10 40.00 206.49 152.96 25.50 81.60 35.707.65 0.10 — 550 (mg) 7.27 37.54 27.81 4.64 14.84 6.49 1.39 0.02 — (wt %)

The dissolution study was carried out using the apparatus, reagents andmethods of the Method 1 dissolution test described above, with thefollowing exceptions: sample timepoints were at 0.5 hour, 1, 2, 3, 6, 1012, 18 and 24 hour. Dissolution results were obtained on the followingTest Capsules: four (n=4) each of formulations OMI-11-0M1-110. The meandissolution data from the ten sets of Test Capsules are summarized belowin Table 21 and depicted in FIGS. 10A and 10B.

TABLE 21 Mean Cumulative Drug Released 0.5 hr 1 hr 2 hr 3 hr 6 hr 10 hr12 hr 18 hr 24 hr Formulation # OMH1  0%  2%  4%  5%  8% 12% 14% 18% 23%Mean 0 2 1 1 1 0 1 1 1 Std Dev Formulation # OMH2 11% 19% 30% 37% 52%64% 69% 82% 91% Mean 0 1 1 1 1 1 1 1 1 Std Dev Formulation # OMH3  0% 1%  4%  6% 11% 18% 21% 30% 36% Mean 0 2 1 1 2 2 3 3 3 Std DevFormulation # OMH4  3%  5%  7%  9% 15% 23% 26% 35% 42% Mean 1 1 1 2 3 33 3 3 Std Dev Formulation # OMH5 11% 17% 27% 33% 48% 61% 66% 78% 87%Mean 1 1 1 1 0 1 1 1 2 Std Dev Formulation # OMH6  2%  4%  7% 10% 19%29% 33% 44% 53% Mean 0 1 1 2 2 3 4 4 4 Std Dev Formulation # OMH7  7%11% 19% 25% 38% 51% 55% 66% 74% Mean 1 1 1 1 2 2 3 3 3 Std DevFormulation # OMH8  7% 12% 19% 25% 39% 52% 57% 69% 76% Mean 1 1 1 1 1 21 3 2 Std Dev Formulation # OMH9  5%  9% 15% 20% 33% 46% 51% 63% 72%Mean 1 2 3 4 6 6 7 5 5 Std Dev Formulation # OMH10  2%  3%  4%  6% 12%23% 29% 45% 57% Mean 1 1 2 2 5 7 8 7 6 Std Dev

Example 3g

The following in vitro dissolution test was carried out to characterizethe in vitro release of abuse-resistant amphetamine oral dosage formsacross several different formulations.

The abuse-resistant amphetamine oral dosage forms used in this Example3g were prepared using the following raw materials: d-AmphetamineSulfate (Cambrex) (“AMP”); Isopropyl Myristate, NF (“IPM”); Colloidalsilicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyltoluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose AcetateIsobutyrate (Eastman Chemicals), (“SAM”); Triacetin USP (“TA”);Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (EastmanChemicals) (“CAB”); Caprylocaproyl Polyoxyglycerides (Gattefosse)(“CPG”); Gelucire 50/13 (Gattefosse) (“GEL”); and Polyethylene Glycol8000 (Dow Chemical) (“PEG 8000”). The formulations were produced using aGMP manufacturing process (Process Scheme 6 as described in Example 1aabove) and then filled into size #1 gel capsules to produce the dosageforms that were used as Test Capsules. The details of the formulationsand the dosage forms containing the formulations of this Example 3g aredisclosed below in Tables 22 and 23.

TABLE 22 Formulation by Weight Percent (wt %) Component AMP1 AMP2 AMP3AMP 7.50 5.45 5.45 SAIB 36.52 36.24 35.16 TA 27.05 26.85 26.04 CAB 4.864.96 4.96 IPM 15.73 16.07 16.07 HEC 5.55 5.67 5.67 SiO₂ 1.85 1.89 1.89BHT 0.02 0.02 0.02 LAB 0.93 0 0 PEG 8000 0 2.84 0 GEL 0 0 4.73

TABLE 23 Formulation by Mass (mg) Component AMP1 AMP2 AMP3 AMP 15.0014.99 14.99 SAIB 73.04 99.66 96.69 TA 54.10 73.84 71.61 CAB 9.72 13.6413.64 IPM 31.46 44.19 44.19 HEC 11.10 15.93 15.59 SiO₂ 3.70 5.20 5.20BHT 0.04 0.06 0.06 LAB 1.86 0 0 PEG 8000 0 7.81 0 GEL 0 0 13.01 Total200.02 275.32 274.98

The dissolution study was carried out using the apparatus, reagents andmethods of the Method 1 dissolution test described above, with thefollowing exceptions: sample timepoints were at 1, 2, 3, 6, 8, 10 12, 18and 24 hour. Dissolution results were obtained on the following TestCapsules: eight (n=8) each of formulations AMP1-AMP3. The meandissolution data from the three sets of Test Capsules are summarizedbelow in Table 24 and depicted in FIG. 11.

TABLE 24 Mean Cumulative Drug Released 1 hr 2 hr 3 hr 6 hr 8 hr 10 hr 12hr 18 hr 24 hr Formulation # AMP1 41% 59% 69% 89% 97% 101% 103% 103%104% Mean 2 3 3 2 3 2 2 2 2 Std Dev Formulation # AMP2 11% 17% 22% 34%42%  48%  53%  66%  75% Mean 1 2 3 3 4 4 4 3 3 Std Dev Formulation #AMP3 34% 49% 59% 79% 88%  95% 100% 105% 106% Mean 3 3 3 3 3 2 2 1 1 StdDev

Example 3h

The following in vitro dissolution test was carried out to characterizethe in vitro release of abuse-resistant methylphenidate oral dosageforms across several different formulations.

The abuse-resistant methylphenidate oral dosage forms used in thisExample 3h were prepared using the following raw materials:methylphenidate (“MPH”); Isopropyl Myristate, NF (“IPM”); Colloidalsilicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyltoluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose AcetateIsobutyrate (Eastman Chemicals), (“SAM”); Triacetin USP (“TA”);Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (EastmanChemicals) (“CAB”); Gelucire 50/13 (Gattefosse) (“GEL”); and Miglyol 812(“MIG”). The formulations were produced using the manufacturing process(Process Scheme 6) as described in Example 1a above, and then filledinto size #3 gelatin capsule shells to produce the dosage forms thatwere used as Test Capsules. The details of the formulations and thedosage forms containing the formulations of this Example 3h aredisclosed below in Tables 25 and 26.

TABLE 25 Formulation by Weight Percent (wt %) MPH1 MPH2 MPH3 MPH4 MPH5MPH6 Component 40 mg 48 mg 48 mg 48 mg 48 mg 48 mg MPH 20.00 20.00 20.0020.00 20.00 20.00 SAIB 33.35 34.31 34.55 34.31 29.25 34.55 TA 22.2322.87 23.03 22.87 20.89 23.03 CAB 4.80 5.20 6.40 5.21 5.58 6.42 IPM13.60 12.80 12.80 12.80 — 12.80 MIG — — — — 16.0 — HEC 0.00 2.40 0.002.40 4.80 — SiO₂ 2.00 1.60 1.60 1.60 1.60 1.60 BHT 0.02 0.02 0.02 0.020.02 0.02 GEL 4.00 0.80 1.60 0.80 1.84 1.60

TABLE 26 Formulation by Mass (mg) MPH1 MPH2 MPH3 MPH4 MPH5 MPH6Component 40 mg 48mg 48 mg 48 mg 48 mg 48 mg MPH 40.00 48.00 48.00 48.0048.00 48.00 SAIB 66.70 82.34 82.92 82.30 70.20 82.90 TA 44.46 54.8955.27 54.90 50.10 55.30 CAB 9.60 12.48 15.36 12.50 13.40 15.40 IPM 27.2030.72 30.72 30.70 — 30.70 MIG — — — — 38.40 — HEC 0.00 5.76 0.00 5.8011.50 — SiO₂ 4.00 3.84 3.84 3.80 3.80 3.80 BHT 0.04 0.05 0.05 0.05 0.050.05 GEL 8.00 1.92 3.84 1.90 4.40 3.80 Total 200.00 240.00 240.00 240.00240.00 240.00

The dissolution study was carried out using the apparatus, reagents andmethods of the Method 1 dissolution test described above, with thefollowing exceptions: sample timepoints were at 0.5 hour, 1, 1.5, 2, 3,6, 9, 12 and 24 hour. Dissolution results were obtained on the followingTest Capsules: four (n=4) each of formulations MPH1 and MPH4-MPH6, andeight (n=8) each of formulations MPH2 and MPH3. The mean dissolutiondata from the six sets of Test Capsules are summarized below in Table27, and depicted in FIGS. 12A and 12B.

TABLE 27 Mean Cumulative Drug Released 0.5 hr 1 hr 1.5 hr 2 hr 3 hr 6 hr9 hr 12 hr 24 hr Formulation # MPH1 15.2%  26.4% 35.1% 42.5% 53.0% 77.6%90.6%  96.3%  98.9% Mean 0.8 0.8 0.9 1.1 1.3 1.7 1.2 0.8 1.0 SDFormulation # MPH2 11.1% 19.27% 26.4% 32.5% 42.0% 62.1% 74.5%  83.1% 94.5% Mean 1.3 2.0 2.8 3.5 4.8 6.2 5.9 5.7 7.0 SD Formulation # MPH3 7.9%  12.0% 15.1% 17.6% 21.6% 31.3% 39.1%  45.7%  64.7% Mean 1.3 2.02.5 3.0 3.6 5.2 6.5 7.9 11.4 SD Formulation # MPH4 15.3%  27.5% 34.8%42.3% 54.0% 78.0% 92.5%  99.5% 104.3% Mean 1.7 3.1 2.2 1.9 2.2 1.4 1.91.3 1.3 SD Formulation # MPH5 15.8%  28.0% 36.9% 44.3% 55.8% 79.3% 93.2%100.7% 104.4% Mean 1.0 1.3 1.3 1.2 1.2 1.4 1.8 2.3 2.8 SD Formulation #MPH6 14.9%  27.6% 37.5% 45.7% 58.5% 84.9% 97.6% 101.7% 104.3% Mean 1.01.4 1.9 2.3 3.2 4.0 2.0 1.0 0.4 SD

Example 4 Analysis of Formulations

(In Vitro Extraction and Volatilization Testing Procedures)

In order to assess the abuse-resistance performance of the dosage formsof the present invention, the following in vitro extraction tests weredeveloped. In particular, intentional abuse of controlled releasepharmaceutical dosage forms will often times be carried out by simpleextraction techniques that can separate most or all of the active agentfrom commercially available controlled release carrier systems usingcommon household solvents. Accordingly, a panel of in vitro extractiontests was developed in order to assess the abuse-resistant performanceof the dosage forms produced according to the instant invention.

Example 4a

In order to assess the abuse-resistance performance of dosage formsproduced according to the present invention, a panel of tests toevaluate extraction of active agent from a dosage form into thefollowing commonly available household solvents was developed asfollows: vinegar (acetic acid), pH 2.5; cola soft drink, pH 2.5; bakingsoda solution (sodium bicarbonate), pH 8.2; 100 proof ethanol (50% v/v);and vegetable oil. The dosage forms of the present invention can betested against this panel of common household solvents at both ambientor “room” temperature (25° C.) and with preheated extraction solvents(heated to 60° C.). In addition, exceptional stressing, such as the useof microwave and freeze-and-crush pretreatment of the dosage forms priorto extraction in the above-noted solvents can also be carried out.

The materials and apparatus used in the solvent extraction panel studyof this Example 4a are as follows. Standard laboratory equipmentincludes a shaker (Jeio Tech Shaking Incubator, Model SI-600), hot waterbath, hot plate, centrifuge, microwave oven, glass mortar and pestle, a250 mL glass bottle with cap, and a filtering unit (0.2 μm nylonmembrane). The solvent reagents used in the extraction panel study areprepared as follows: distilled water; 200 proof ethanol (Spectrum) mixedin equal parts distilled water to provide 100 proof ethanol solvent;distilled white vinegar 5% acidity (Heinz); cola soft drink (Coke ColaClassic); vegetable oil (Canola); baking soda (Arm & Hammer), saturatedsolution prepared by adding 527 g of baking soda to 2 L distilled water,mixed vigorously for approximately 1 hour, allowed to settle and thenfiltered the supernatant using the 0.2 μm nylon membrane. The pH of theVinegar, cola soft drink and saturated baking soda solution aredetermined using a pH meter and recorded prior to extraction studies.

The test procedures used for all of the solvents except the vegetableoil solvent are as follows. 240 mL of each extraction solvent is placedinto separate extraction bottles. A dosage form is then added (if thedosage form is a solid tablet, the form is crushed and then dropped intothe solvent, if the dosage form is a liquid capsule, the capsule is cutto open the shell, and the liquid contents are squeezed from the capsuleinto the solvent, and then the empty shell is dropped into the solvent).Extraction is initiated on the shaker using a constant speed of 150 rpm.Samples (1 mL) are withdrawn at 5-, 20- and 60-minute time points. Thesamples are centrifuged at 10,000 rpm for 10 minutes, and about 0.5 mLof the supernatant is transferred into HPLC vials for analysis (HP Model1200 or similar model). This extraction panel is then repeated whereinthe extraction solutions are pre-warmed in a 60° C. water bath. Theactual initial and final temperatures of the solvent solution are thentaken.

The test procedures used for the vegetable oil solvent are as follows. 2tablespoons of the oil is placed into an extraction bottle. A dosageform is then added (if the dosage form is a solid tablet, the form iscrushed and then dropped into the solvent, if the dosage form is aliquid capsule, the capsule is cut to open the shell, and the liquidcontents are squeezed from the capsule into the solvent, and then theempty shell is dropped into the solvent). Extraction is initiated on theshaker using a constant speed of 150 rpm. Samples (1 mL) are withdrawnat 5-, 15-, 30- and 60-minute time points. The samples are centrifugedat 10,000 rpm for 10 minutes, and about 0.5 mL of the supernatant istransferred into HPLC vials for analysis (HP Model 1200 or similarmodel).

For the exceptional stressing test (microwave, and freeze-and-crushpretreatment of the dosage forms prior to extraction in the above-notedsolvents), the test procedures are as follows. For the microwave stressanalysis, dosage forms are added to empty extraction bottles (if thedosage form is a solid tablet, it is crushed and then dropped into thebottle, if the dosage form is a liquid capsule, the capsule is cut toopen the shell, and the liquid contents are squeezed from the capsuleinto the bottle). The extraction bottles (4 at a time) are thenmicrowaved for 2 min with power level set at “High” (power=90). Uponremoval from the microwave, the appearance of the dosage form isrecorded. Next, either 240 mL of distilled water or 240 mL of the100-proof ethanol solvent is added to the extraction bottle (to assessextraction into water or ethanol). Extraction is initiated on the shakerusing a constant speed of 150 rpm. Samples (1 mL) are withdrawn at 5-,20- and 60-minute time points. The samples are centrifuged at 10,000 rpmfor 10 minutes, and about 0.5 mL of the supernatant is transferred intoHPLC vials for analysis (HP Model 1200 or similar model). Thisextraction procedure is then repeated on untested dosage forms afterthey have been allowed to equilibrate to room temperature (˜1.5 hr)after microwave treatment.

For the freeze-and-crush (physical and mechanical stress) analysis,dosage forms are stored in tact in a −80° C. freezer overnight (18 hrs).The test samples are then removed from the freezer and kept on dry iceuntil they are ready to be ground up. The frozen dosage forms are thenplaced into a freezer bag (about 9×12 cm) and crushed by pressingimmediately in a glass mortar and pestle. Any excess (non-formulationcontaining) portion of the freezer bag is then removed to provide abouta 9×9 cm test article that is quantitatively transferred (with theremaining freezer bag) into an extraction bottle. Next, either 240 mL ofdistilled water or 240 mL of the 100-proof ethanol solvent is added tothe extraction bottle (to assess extraction into water or ethanol).Extraction is initiated on the shaker using a constant speed of 150 rpm.Samples (1 mL) are withdrawn at 5-, 20- and 60-minute time points. Thesamples are centrifuged at 10,000 rpm for 10 minutes, and about 0.5 mLof the supernatant is transferred into HPLC vials for analysis (HP Model1200 or similar model).

In order to assess the abuse-resistance performance of a pharmaceuticaldosage form produced according to the present invention in this Example4a, the above-described extraction panel tests were carried out toassess a formulation produced according to Example 2 above. Inparticular, the following raw materials were used to create formulationsfor use in the extraction study: Oxycodone base, micronized (“OXY”);Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®,Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingProcess Scheme 4 (as described above) and then filled into size 00 whiteopaque gel cap shells to produce 40 mg dosage forms that were used asTest Capsules. The details of the formulations of this Example 4a aredisclosed below in Table 28.

TABLE 28 OXY SAIB TA CAB IPM HEC SiO₂ BHT (wt %) (wt %) (wt %) (wt %)(wt %) (wt %) (wt %) (wt %) 5.13 40.98 27.32 4.74 14.23 5.69 1.9 0.02

As a Control, controlled release tablet dosage forms were sourced asOxyContin brand controlled release oxycodone tablets, 40 mg (PurduePharma, lot# W49E1, expiration date January 2009) and run in the samepanel of tests. The pH of the cola soft drink, vinegar, and saturatedbaking soda solution at room temperature, prior to extraction, werefound to be 2.49, 2.47 and 8.23, respectively.

The overall kinetics of oxycodone extraction from the Test Capsules(produced according to the invention) and the Control (OxyContin)tablets in a panel of household solvents at ambient temperature (RT) isdepicted in FIG. 13. As can be seen, the level of oxycodone releasedtails off for all groups after the 20-minute extraction point; however,the Control (OxyContin) tablets are prone to immediate release (rangingfrom 37 to 88%) compared to a range of just 1.4-3.3% for the TestCapsules at the 5-minute time point. With the sole exception ofextraction in the saturated baking soda solvent, oxycodone extractedfrom the Control tablets was quantitative at the 60-minute extractiontime point (100% extraction). Conversely, the amount of oxycodoneextracted from the Test Capsules was only approximately 20% in the colasoft drink, and only 10% in other the solvents at the 60-minuteextraction time point.

The overall kinetics of oxycodone extraction from the Test Capsules andthe Control tablets in a panel of household solvents at elevatedtemperature (60° C.) is depicted in FIG. 14. The temperature of thesolvents prior to extraction was measured at 62° C. prior to extraction,and 33° C. at the 60-minute extraction time point. As can be seen, theextraction of oxycodone again tails off for all groups after the20-minute extraction point, and the Control tablets are prone toimmediate release (from 64 to 96% compared to just 9-28% for the TestCapsules) at the 5-minute time point. In addition, in all solventsexcept the saturated baking soda solvent, oxycodone extraction from theControl tablets was quantitative at the 60-minute extraction time point(100% extraction). Conversely, the amount of oxycodone extracted fromthe Test Capsules was only approximately 42% in the cola soft drink, andonly from 18 to 25% in other the solvents at the 60-minute extractiontime point.

The numerical results of the extraction panel study of this Example 4a,including the results discussed above and depicted in FIGS. 13 and 14,are reported below in Table 29. As can be seen, formulations producedaccording to the present invention can be used to provideabuse-resistant oral pharmaceutical dosage forms that exhibit superiorabuse-resistant performance across a panel of solvent extraction tests.

TABLE 29 Test Capsule Control tablet Extraction Extraction (% oxycodoneextracted) (% oxycodone extracted) Stress Method temp. solvent 5 min 60min 5 min 60 min Mechanical RT Water  2.6 ± 0.8¹ 13.5 ± 4.6 — — Stress100-proof 10.4 ± 5.9   32.0 ± 13.3 — — ethanol Multiple RT Vinegar 1.4 ±0.5 11.4 ± 1.2 85.9 ± 0.8 96.6 ± 2.2 Solvent Coke 3.3 ± 2.3 21.8 ± 0.287.5 ± 2.7 98.7 ± 0.1 Extraction Sat'd baking 1.7 ± 0.1 10.7 ± 2.3 37.3± 1.0 59.5 ± 1.2 Conditions soda 100-proof 1.5 ± 0.1 10.3 ± 0.1 34.6 ±3.3 96.9 ± 7.0 ethanol vegetable oil 2.52 3.37 — — 62-33° C.² Vinegar8.9 ± 2.3 18.1 ± 2.0 95.6 ± 2.2 97.3 ± 1.9 Coke 27.7 ± 1.6  42.2 ± 3.492.0 ± 2.1 96.0 ± 0.5 Sat'd baking 9.3 ± 2.7 20.8 ± 3.4 63.7 ± 0.8 84.1± 1.2 soda 100-proof 9.5 ± 1.0 25.2 ± 0.4  71.5 ± 17.7  98.5 ± 0.01ethanol Microwave RT/ Water 7.8 ± 4.9 24.8 ± 9.5 75.5 ± 4.5 95.9 ± 1.4Immediate 100-proof 14.6 ± 5.7  36.1 ± 8.1 — — Extraction ethanolRT/plus cool Water 1.1 ± 0.1 14.0 ± 1.8 — — off 100-proof 1.1 ± 0.5 17.8 ± 10.2 — — ethanol ¹average ± standard derivation ²initial andfinal temperature, respectively

In order to further assess the abuse-resistance performance of thedosage forms of the present invention, the following in vitrovolatilization test was developed. In particular, intentional abuse ofcontrolled release pharmaceutical dosage forms may alternatively becarried out by volatilization (smoking, or free-basing) techniques thatcan liberate active agent (in immediately active form) from commerciallyavailable controlled release carrier systems. Accordingly, a preliminaryin vitro volatilization test was developed in order to assess: (1)whether oxycodone free base was more volatile than the salt (HCl) form;and (2) whether the abuse-resistant dosage forms produced according tothe instant invention can prevent inhalation abuse throughvolatilization.

For the study, 40 mg of neat active agent (oxycodone in free base form,oxycodone in HCl salt form), 40 mg Test Capsules (produced as describedabove) and 40 mg SR Control (OxyContin brand controlled releaseoxycodone tablets) were weighed into individual petri dishes. Each petridish was fitted with a watch glass as a cover, and the covered testdishes were placed on a hot plate (setting 10). After 30 seconds eachwatch glass was replaced with a fresh watch glass, and this step wasrepeated three times (to obtain 4 time points). Any residue deposited onthe bottom side of the test watch glasses was carefully transferred withan Alpha Swab (TX 761) into 40/60 ethanol/0.005M HCl solution, and theconcentration of oxycodone solution was determined by HPLC. Theobservations taken during the test were as follows. The neat base formactive agent (oxycodone free base form) vaporizes/sublimes upon heating,whereas there was extensive degradation and charring of the salt formactive agent (oxycodone HCl), the Test Capsules, and the SR Controltablets. It was noted that vaporized drug (and solvents where present)escaped during each change of the watch glass, which may be at leastpartially responsible for the low recovery noted in the HPLC resultsbelow. In addition, the presence of solvents and other excipients in theTest Capsules made it difficult to volatilize the oxycodone activeagent, and there was a particularly noxious smell noted when the TestCapsules were volatilized. The HPLC results obtained in this Example 4aare provided below in Table 30.

TABLE 30 Time Point Oxycodone Collected Test Sample (minutes) (in mg) %Recovery oxycodone API 0.5 1.4730 (free base form) 1.0 7.2666 1.5 0.73562.0 0.7050 (total): 10.1802 24.0% oxycodone API 0.5 1.7202 (HCl saltform) 1.0 0.4086 1.5 0.1236 2.0 0.0270 (total): 2.2794  5.7% TestCapsule 0.5 0.0048 1.0 0.1206 1.5 0.9732 2.0 1.1478 (total): 2.2464 5.6% SR Control 0.5 1.8144 1.0 3.0624 1.5 0.2928 2.0 0.084 (total):5.2536 14.7%

As can be seen from these results, the free base form of oxycodone(neat) volatilizes more readily than the neat HCl salt form. However,once sequestered within the controlled release system of the presentinvention, the oxycodone free base is volatilized to a much lowerextent. Accordingly, although the current volatilization test proceduremay not provide a quantitative measure, it is useful to provide relativemeasures of the degree to which a dosage form is subject to abuse usingsuch techniques.

Example 4b

The following in vitro Abuse Resistance Evaluation was carried out tocharacterize the in vitro abuse resistance performance of dosage formsprepared according to the present invention: (a) following influence ofphysical, chemical or mechanical stress; and (b) via inhalation, whereinboth sets of test procedures are compared to a commercially availableproduct. More particularly, 3 different manufacturing lots ofabuse-resistant oxycodone oral dosage 40 mg strength forms produced withdifferent purity grades of the active agent (oxycodone) were used as theTest Capsules. OxyContin brand (oxycodone HCl controlled-release)Tablets, 40 mg strength (Lot W28A1, Purdue Pharma L.P.) were used as thecommercial comparison.

The abuse-resistant oxycodone oral dosage forms used in this Example 4bwere prepared using the following raw materials: Oxycodone base,micronized (“OXY”), grade 2 (specified to contain not more than 0.25%(w/w) 14-hydroxycodeinone (14-HC)) or grade 1 (specified to contain notmore than 0.001% (w/w) 14-HC), both grades obtained from Noramco, Inc(Athens Ga.); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize #00 hard gelatin cap shells to produce the 40 mg dosage forms thatwere used as Test Capsules. The details of the formulations and thedosage forms containing the formulations of this Example 4b aredisclosed below in Table 31.

TABLE 31 OXY SAIB TA CAB IPM HEC SiO₂ BHT (total) 5.13 40.98 27.32 4.7414.23 5.69 1.9 0.02 (wt %) 40.0 319.6 213.1 37.0 111.0 44.4 14.8 0.16780.0 (mg)

The in vitro abuse resistance results were obtained on the followingTest Capsules: three 40 mg dosage forms (n=3), containing grade 2oxycodone and selected as exhibiting the fastest dissolution rate fromdissolution testing described in Example 3 above (OXY1); three 40 mgdosage forms (n=3), containing grade 2 oxycodone and selected asexhibiting the slowest dissolution rate from dissolution testingdescribed in Example 3 above (OXY2); and three 40 mg dosage forms (n=3),containing grade 1 oxycodone (OXY3). The commercial comparison wasagainst three 40 mg OxyContin (SR Control) tablets (n=3).

The in vitro abuse resistance study was carried out substantially thesame as in Example 4a above, using the same apparatus, reagents andmethods described above, with any exceptions noted as follows.Initially, extraction of the oxycodone active agent from the TestCapsules and the SR Control tablets by four commercial beverages orcommon household liquids/preparations was assessed, where the fourselected solvents were chosen based on their ubiquity and to span theacidic and alkaline pH range; i.e., vinegar (pH 2.5); cola soft drink(pH 2.4); hot tea (ranges pH 4.6-5.1, 65° C.-70° C.); and saturatedbaking soda in water (range pH 8.3-0.1). These selected solvents arereadily accessible to potential abusers and constitute an assortment ofnon-toxic drinkable liquids that may be used to facilitate abuse. TestCapsules were cut open and squeezed to exude the liquid contents andassure intimate contact of test solvents with the controlled releasematrix. The SR Control tablets were ground for 3 minutes with mortar andpestle to disrupt the controlled release matrix prior to placement intesting jars. The Test Capsules and treated SR Control tablets wereplaced into test jars containing 240 mL of each solvent. The closed jarswere vigorously shaken at 100 rpm for 60 minutes, with shakinginterrupted to withdraw samples at 5, 20 and 60 minutes. The solventsamples taken at each testing interval were centrifuged and assayed foroxycodone content by HPLC. The extraction results are provided in Tables32 to 35 below, and in FIG. 15.

TABLE 32 Amount of Oxycodone Extracted in Vinegar (% of dose) Time (min)Sample ID 5 20 60 OXY1-a 0 2 11 OXY1-b 0 2 10 OXY1-c 0 1 9 OXY2-a 0 1 8OXY2-b 0 1 10 OXY2-c 1 2 12 OXY3-a 0 2 10 OXY3-b 0 2 9 OXY3-c 0 3 12 SRControl-a 87 89 89 SR Control-b 90 92 92 SR Control-c 93 94 94 Mean(SD), Test Capsules  0 (0.2)  2 (0.6) 10 (1.3) Mean (SD), SR Control 90(3.0) 92 (2.5) 92 (2.5)

TABLE 33 Amount of Oxycodone Extracted in Cola (% of dose) Time (min)Sample ID 5 20 60 OXY1-a 1 3 10 OXY1-b 1 4 12 OXY1-c 1 2 11 OXY2-a 0 210 OXY2-b 1 2 8 OXY2-c 0 3 10 OXY3-a 1 2 10 OXY3-b 1 4 12 OXY3-c 2 6 12SR Control-a 94 94 95 SR Control-b 86 86 86 SR Control-c 93 96 96 Mean(SD), Test Capsules  1 (0.6)  3 (1.3) 10 (1.4) Mean (SD), SR Control 91(4.4) 92 (5.3) 92 (5.5)

TABLE 34 Amount of Oxycodone Extracted in Hot Tea (% of dose) Time (min)Sample ID 5 20 60 OXY1-a 7 11 16 OXY1-b 4 8 11 OXY1-c 6 10 14 OXY2-a 1116 19 OXY2-b 3 7 11 OXY2-c 3 7 11 OXY3-a 8 14 19 OXY3-b 6 10 14 OXY3-c 813 16 SR Control-a 48 51 53 SR Control-b 61 65 63 SR Control-c 70 71 71Mean (SD), Test Capsules 6 (2.6) 11 (3.2)  15 (3.3) Mean (SD), SRControl 60 (11.1) 62 (10.3) 62 (9.0)

TABLE 35 Amount of Oxycodone Extracted in Sat. Baking Soda (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 1 2 4 OXY1-b 1 2 5 OXY1-c 1 2 5OXY2-a 1 1 3 OXY2-b 0 1 2 OXY2-c 0 1 2 OXY3-a 1 1 3 OXY3-b 1 2 3 OXY3-c1 2 3 SR Control-a 62 72 71 SR Control-b 80 81 81 SR Control-c 81 81 80Mean (SD), Test Capsules 1 (0.5)  2 (0.6)  3 (1.1) Mean (SD), SR Control74 (10.7) 78 (5.2) 77 (5.5)

As can be seen by these solvent extraction results, the Test Capsulesresisted extraction in all test solvents over the course of 60 minuteswith agitation. After 5 minutes, 1% or less of the oxycodone wasextracted from the Test Capsules in the cola, vinegar and saturatedbaking soda solution, as compared to 90% or greater from the SR Controltablets in cola and vinegar, and about 75% from the SR Control tabletsin saturated baking soda solution. The greatest mean extraction 96% or2.4 mg) of oxycodone from the Test Capsules at the 5 minute pointoccurred in hot tea. By comparison, extraction from the SR Controltablets in hot tea was ten fold higher (60%, or 24 mg). Extraction ofoxycodone from the Test Capsules slightly increased in all solvents overthe course of 60 minutes. In comparison, extraction from the SR Controltablets mostly occurred within 5 minutes and remained fairly constantfor the remainder of the test, strongly suggesting dose dumping. Thehighest mean amount of oxycodone extracted from the Test Capsules (15%,or 6 mg) occurred after 60 minutes in hot tea.

Next, extraction of the oxycodone active agent from the Test Capsulesand the SR Control tablets by each of six aqueous buffers over a rangeof pH 1-pH 12 was assessed. Specific buffer strengths were pH 1, pH 4,pH 6, pH 8, pH 10 and pH 12. The pH 1 buffer consisted of 0.1N HCl, thepH 4 buffer consisted of 5 mM acetate, and buffers of Ph 6, 10 and 12consisted of 5 mM phosphate. Test Capsules were cut open and squeezed toexude the liquid contents and assure intimate contact of test solventswith the controlled release matrix. The SR Control tablets were groundfor 3 minutes with mortar and pestle to disrupt the controlled releasematrix prior to placement in testing jars. The Test Capsules and treatedSR Control tablets were placed into test jars containing 240 mL of eachbuffer. The closed jars were vigorously shaken at 100 rpm for 60minutes, with shaking interrupted to withdraw samples at 5, 20 and 60minutes. The solvent samples taken at each testing interval werecentrifuged and assayed for oxycodone content by HPLC. The extractionresults are provided in Tables 36 to 41 below, and in FIG. 16.

TABLE 36 Amount of Oxycodone Extracted in Aq Buffer, pH 1 (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 2 5 13 OXY1-b 1 3 12 OXY1-c 1 3 10OXY2-a 1 4 13 OXY2-b 1 4 10 OXY2-c 1 3 10 OXY3-a 1 5 15 OXY3-b 1 4 14OXY3-c 2 6 14 SR Control-a 89 93 94 SR Control-b 80 88 91 SR Control-c81 82 83 Mean (SD), Test Capsules  1 (0.4)  4 (0.9) 12 (2.0) Mean (SD),SR Control 83 (4.9) 88 (5.5) 89 (5.7)

TABLE 37 Amount of Oxycodone Extracted in Aq Buffer, pH 4 (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 1 2 5 OXY1-b 2 4 9 OXY1-c 1 3 7OXY2-a 1 3 7 OXY2-b 1 3 8 OXY2-c 2 2 7 OXY3-a 1 3 8 OXY3-b 1 2 6 OXY3-c2 4 9 SR Control-a 85 94 95 SR Control-b 89 89 90 SR Control-c 85 90 91Mean (SD), Test Capsules  1 (0.5)  3 (0.7)  7 (1.3) Mean (SD), SRControl 86 (2.3) 91 (2.6) 92 (2.6)

TABLE 38 Amount of Oxycodone Extracted in Aq Buffer, pH 6 (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 2 2 6 OXY1-b 0 2 4 OXY1-c 1 2 6OXY2-a 1 3 7 OXY2-b 1 2 5 OXY2-c 1 2 6 OXY3-a 1 2 6 OXY3-b 2 5 12 OXY3-c1 3 10 SR Control-a 78 91 91 SR Control-b 79 85 85 SR Control-c 80 91 93Mean (SD), Test Capsules  1 (0.6)  3 (1.0)  7 (2.4) Mean (SD), SRControl 79 (1.0) 89 (3.5) 90 (4.2)

TABLE 39 Amount of Oxycodone Extracted in Aq Buffer, pH 8 (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 1 2 4 OXY1-b 1 2 4 OXY1-c 1 2 4OXY2-a 2 3 5 OXY2-b 1 2 5 OXY2-c 1 3 7 OXY3-a 1 3 6 OXY3-b 1 2 4 OXY3-c1 3 7 SR Control-a 91 91 92 SR Control-b 86 89 89 SR Control-c 90 91 91Mean (SD), Test Capsules  1 (0.5)  2 (0.6)  5 (1.2) Mean (SD), SRControl 89 (2.6) 90 (1.2) 91 (1.5)

TABLE 40 Amount of Oxycodone Extracted in Aq Buffer, pH 10 (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 1 1 4 OXY1-b 1 2 5 OXY1-c 1 3 6OXY2-a 0 1 4 OXY2-b 0 2 4 OXY2-c 0 2 4 OXY3-a 0 2 4 OXY3-b 0 2 5 OXY3-c1 2 5 SR Control-a 82 87 88 SR Control-b 83 88 89 SR Control-c 80 88 88Mean (SD), Test Capsules  0 (0.5)  2 (0.5)  4 (0.8) Mean (SD), SRControl 82 (1.5) 88 (0.6) 88 (0.6)

TABLE 41 Amount of Oxycodone Extracted in Aq Buffer, pH 12 (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 0 1 3 OXY1-b 0 1 3 OXY1-c 0 1 3OXY2-a 1 2 4 OXY2-b 0 1 3 OXY2-c 0 1 3 OXY3-a 0 1 3 OXY3-b 0 1 4 OXY3-c0 1 3 SR Control-a 65 70 71 SR Control-b 71 73 75 SR Control-c 57 65 69Mean (SD), Test Capsules  0 (0.3)  1 (0.2)  3 (0.4) Mean (SD), SRControl 64 (7.0) 69 (4.0) 72 (3.1)

As can be seen by these buffer extraction results, all Test Capsuleswere resistant to extraction of oxycodone in all buffers over the courseof 60 minutes with agitation. After five minutes, 1% or less of theoxycodone active agent was extracted in pH 1-12 aqueous buffers ascontrasted with 64% or greater from the SR Control tablets. The amountof oxycodone extracted from the Test Capsules was seen to decrease withincreasing pH. The greatest mean oxycodone extraction form the TestCapsules was 12% (4.8 mg) in pH 1 buffer after 60 minutes, as comparedwith 89% mean oxycodone extraction (35.6 mg) from the SR Controlcomparison. Finally, whereas extraction of oxycodone from the TestCapsules in all buffers increased slightly with time, virtually completedose dumping of oxycodone from the SR Control tablets occurred withinthe first 5 minutes (83% or 33.2 mg) and remained fairly constant forthe remainder of the test.

Continuing with the study, extraction of the oxycodone active agent fromthe Test Capsules and the SR Control tablets following physicaldisruption was determined. In particular, the Test Capsules were chilledin dry ice for 16 to 20.5 hours to promote any tendency for freezing orbrittleness of the formulation. Each chilled capsule was then placedimmediately within the fold of a plastic film and ground in a mortar andpestle for 3 minutes. Enclosing the capsule within the folds of plasticfilm during grinding prevented loss of test material due to the tendencyfor product residue to stick to the mortar and pestle. Each SR Controltablet was also crushed and ground in a mortar and pestle. Threeextraction solvents including water heated to 60-70° C. and at ambient(25° C.) temperature, 0.1N HCl, and 100 proof ethanol were used for theextraction solvents. The physically disrupted samples were placed intotesting jars containing 240 mL of the various solvents. The closed jarswere vigorously shaken at 100 rpm for 60 minutes, with shakinginterrupted to withdraw samples at 5, 20 and 60 minutes. The solventsamples taken at each testing interval were centrifuged and assayed foroxycodone content by HPLC. The extraction results are provided in Tables42 to 45 below, and in FIG. 17.

TABLE 42 Amount of Oxycodone Extracted in Water, 25° C. (% of dose) Time(min) Sample ID 5 20 60 OXY1-a 1 7 17 OXY1-b 2 7 15 OXY1-c 1 8 17 OXY2-a6 12 22 OXY2-b 6 11 21 OXY2-c 7 15 27 OXY3-a 2 8 18 OXY3-b 3 8 16 OXY3-c1 4 8 SR Control-a 90 92 92 SR Control-b 87 87 88 SR Control-c 87 88 88Mean (SD), Test Capsules  3 (2.4)  9 (3.3) 18 (5.2) Mean (SD), SRControl 88 (1.7) 89 (2.6) 89 (2.3)

TABLE 43 Amount of Oxycodone Extracted in Water, 60-70° C. (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 9 25 36 OXY1-b 11 19 26 OXY1-c 12 3145 OXY2-a 13 22 30 OXY2-b 15 27 38 OXY2-c 12 22 32 OXY3-a 7 18 28 OXY3-b10 19 26 OXY3-c 9 17 23 SR Control-a 90 94 94 SR Control-b 92 93 92 SRControl-c 88 88 88 Mean (SD), Test Capsules 11 (2.3) 22 (4.7) 32 (7.0)Mean (SD), SR Control 90 (2.)  92 (3.2) 91 (3.1)

TABLE 44 Amount of Oxycodone Extracted in 0.1N HCl (% of dose) Time(min) Sample ID 5 20 60 OXY1-a 4 14 27 OXY1-b 4 16 27 OXY1-c 2 15 27OXY2-a 18 22 32 OXY2-b 16 22 31 OXY2-c 13 18 27 OXY3-a 11 21 34 OXY3-b 919 31 OXY3-c 10 20 32 SR Control-a 88 92 89 SR Control-b 93 94 94 SRControl-c 84 89 92 Mean (SD), Test Capsules 10 (5.6) 19 (3.2) 30 (2.9)Mean (SD), SR Control 88 (4.5) 92 (2.5) 92 (2.5)

TABLE 45 Amount of Oxycodone Extracted in 100 Proof Ethanol (% of dose)Time (min) Sample ID 5 20 60 OXY1-a 8 18 33 OXY1-b 7 9 30 OXY1-c 13 1929 OXY2-a 9 26 42 OXY2-b 10 27 42 OXY2-c 9 23 37 OXY3-a 4 22 36 OXY3-b 419 32 OXY3-c 9 21 35 SR Control-a 79 87 93 SR Control-b 82 90 93 SRControl-c 72 86 93 Mean (SD), Test Capsules  8 (3.0) 20 (5.2) 35 (4.5)Mean (SD), SR Control 78 (5.1) 88 (2.1) 93 (0.0)

During testing it was note that the Test Capsules maintain their fluidcharacteristics even at temperatures as low as those employed in thistest. Although the gelatin capsule shell fractures as a result of thecrushing and grinding, the formulations from the capsules remain as ahigh viscosity liquid. It is thus believed that the formulations of thepresent invention are not susceptible to techniques that may be used tocrush or grind traditional controlled release dosage forms. As can beseen by the solvent extraction results, the Test Capsules resisted rapidrelease of oxycodone even after chilling, crushing, grinding andexposure to an extraction solvent. The amount of extracted oxycodoneafter 60 minutes ranged from 18% in water to 35% in the 100 proofethanol solution. Cumulative extraction was seen to gradually increasewith time in all extraction solvents, with no evidence of rapid releaseor dose dumping. These data thus suggest that the instantabuse-resistant dosage forms strongly resist extraction of the activeingredient (oxycodone) even after aggressive physical disruption.Furthermore, the sticky liquid mass that is obtained was found difficultto handle. In contrast, crushing and grinding the SR Control tablets inthis test clearly results in a compromise of its solid controlledrelease matrix. In this regard, from 70 to 90% of the oxycodone dose wasextracted in each of the extraction solvents after only 5 minutes, withslight increases thereafter.

Next, extraction of oxycodone from the test capsules and the SR Controltablets using canola oil was assessed. Intimate contact of theextraction oil with the Test Capsule formulations was ensured by cuttingopen the capsules and squeezing the contents into the oil. Each SRControl tablet was crushed and ground in a mortar and pestle for 3minutes. The contents of the Test Capsules and the processed SR Controltablets were placed in 10 mL of canola oil. This volume of oil wasselected since routine ingestion of a larger amount of oil would have alaxative effect and therefore was considered impractical. The closedjars were vigorously shaken at 100 rpm for 60 minutes, with shakinginterrupted to withdraw samples at 30 and 60 minutes. The solventsamples taken at each testing interval were centrifuged and assayed foroxycodone content by HPLC. The results of the study showed that neitherthe Test Capsules nor the SR Control tablets demonstrated extractioninto vegetable oil since not more than 1% of oxycodone was extractedfrom either dosage form. These data suggest that canola oil is not agood solvent for oxycodone base or oxycodone HCl, and such a test islikely inconclusive for dosage forms containing this active agent.

Continuing with the study, extraction of oxycodone from the TestCapsules following heating by microwave radiation was determined. EachTest Capsule was heated in a sample jar for 2 minutes at high powersetting (1250 watts) in a household microwave oven. Microwave heatingcaused the liquid contained within the Test Capsules to melt thought thegelatin capsule, and in many cases, the heated liquid mass also causedthe capsule to explode. A volume of 240 mL of the following test liquidswas then added to each test jar: water (25° C.), 0.1N HCl, and 100 proofalcohol solution. The closed jars were vigorously shaken at 100 rpm for60 minutes, with shaking interrupted to withdraw samples at 5, 20 and 60minutes. The solvent samples taken at each testing interval werecentrifuged and assayed for oxycodone content by HPLC. The extractionresults are provided in Tables 46 to 48 below, and in FIG. 18.

TABLE 46 Amount of Oxycodone Extracted in Water after Microwaving (% ofdose) Time (min) Sample ID 5 20 60 OXY1-a 3 6 12 OXY1-b 8 14 29 OXY1-c 15 10 OXY2-a 2 6 12 OXY2-b 0 3 9 OXY2-c 1 7 12 OXY3-a 1 6 12 OXY3-b 2 715 OXY3-c 3 7 15 Mean (SD), Test Capsules 2 (2.2) 7 (3.0) 14 (5.9)

TABLE 47 Amount of Oxycodone Extracted in 100 Proof Ethanol afterMicrowaving (% of dose) Time (min) Sample ID 5 20 60 OXY1-a 2 8 11OXY1-b 4 4 19 OXY1-c 5 11 24 OXY2-a 4 13 26 OXY2-b 6 8 26 OXY2-c 1 3 8OXY3-a 2 7 17 OXY3-b 15 19 35 OXY3-c 2 7 16 Mean (SD), Test Capsules 4(4.2) 9 (4.8) 20 (8.3)

TABLE 48 Amount of Oxycodone Extracted in 0.1N HCl after Microwaving (%of dose) Time (min) Sample ID 5 20 60 OXY1-a 3 6 13 OXY1-b 6 17 28OXY1-c 6 13 26 OXY2-a 1 8 18 OXY2-b 4 8 12 OXY2-c 1 4 10 OXY3-a 8 16 27OXY3-b 7 15 23 OXY3-c 4 12 21 Mean (SD), Test Capsules 4 (2.6) 11 (4.6)20 (6.9)

As can be seen by these extraction results, only 4% (1.6 mg) or less ofthe oxycodone dose was extracted from the microwaved Test Capsules after5 minutes of extraction in each of the extraction liquids. After 60minutes, only about 14-10% of the oxycodone dose was extracted in anytest liquid. These data show that the Test Capsules resist rapidextraction or dose dumping of the active agent (oxycodone) in commonhousehold liquids even following extreme thermal stress.

Example 4c

The following in vitro Injection Abuse Resistance Evaluation was carriedout to characterize the ability of abuse-resistant formulations preparedaccording to the present invention to resist injection-based forms ofabuse. In this regard, the characteristics of an injectable suspensionare defined as syringeability and injectability. Syringeability pertainsto the ability of a suspension to be drawn into an empty syringe througha hypodermic needle, while injectability address the ability of asuspension to be pushed from a pre-filled syringe through a hypodermicneedle. Both characteristics depend upon the viscosity and physicalcharacteristics of a test formulation.

For the test, placebo (no active agent) formulations were evaluated forsyringeability and injectability to assess resistance to abuse byinjection. The placebo formulations used in this Example 4c wereprepared using the following raw materials: Isopropyl Myristate, NF(“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”);Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF(“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAM”);Triacetin USP (“TA”); and Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”). The placebo formulationswere produced using the commercial-scale manufacturing methods (ProcessSchemes 4 or 5 as described above) and filled into gelatin capsuleshells (size #00) to produce Test Capsules. The details of the placeboformulation used in this Example 4c are disclosed below in Table 49.

TABLE 49 SAIB TA CAB IPM HEC SiO₂ BHT (total) 43.19 28.80 5.0 15.0 6.02.0 0.02 (wt %) 319.6 213.1 37.0 111.0 44.4 14.8 0.16 740.0 (mg)

The test equipment and apparatus used in this study included syringebarrel (Becton Dickinson (B-D) 3 mL Disposable Syringe with Leur-LokTip; hypodermic needles (B-D (305136) PrecisionGlide Needle 27G1.25; B-D(305125) PrecisionGlide Needle 25G1; B-D (305190) PrecisionGlide NeedleIV 1.5, 21G; B-D (305185) PrecisionGlide Needle Fill 1.5, 18G); and anInstron 5542 Load Frame, controlled by BLUEHILL software.

Initially, syringeability was assessed in two ways: first by attemptingto draw the placebo formulation from a Test Capsule by piercing thecapsule shell with the hypodermic needle and attempting to draw theformulation into the syringe; and second, by attempting to squeeze theformulation from a cut capsule into the posterior end of a syringebarrel (i.e., with the plunger removed). The syringeability analysis wasconducted using placebo formulations equilibrated at room temperature(25° C.). Both of these techniques represent practices that may beemployed by a drug abuser. Any placebo formulation mass successfullydrawn or filled into the syringe was quantified and recorded.

Injectability was evaluated using the Instron Load Frame instrument topush the plunger of a pre-loaded syringe in an attempt to deliver theplacebo formulation. The force required for successful injection of theplacebo formulation or the force at which failure occurred was recordedby the instrument. The single-use syringe barrels were filled withapproximately 1 g of the placebo formulation (range 0.64 to 1.14 g).Entrapped air was removed by application of vacuum while depressing theplunger to minimize variability in the injectability analysis. Testingwas performed on two sets of placebo formulations that were equilibratedto either 25° C. or 37° C. Needles with gauge sizes of 18, 21, 25 and 27were joined by a Luer-Lok fitting to the pre-loaded syringe barrel.Three different crosshead speeds (i.e., plunger depression rates) wereevaluated for each needle gauge. Crosshead speeds of 150 mm/min, 550mm/min, and 950 mm/min were selected based upon documented typicalinjection rates for parenteral administration. Three samples were testedat each set of conditions.

The results of this abuse-resistance test were as follows.Syringeability: it was not possible to draw the placebo formulation intothe syringe using the largest bore needle (18 gauge) due to the highviscosity and thixotropy of the formulation. As a result, evaluationusing smaller bore needles (21, 25 and 27 gauge) were not performed.Placebo formulation at room temperature was squeezed from an openedcapsule into the posterior end of a tared syringe barrel. The weightssuccessfully transfereed into each of five syringes was recorded. A meanweight of 0.42 g (range 0.22-0.50 g, mean of 54%, range 28-64%) wastransferred from the Test Capsules. Accordingly, syringeability was notachieved for any gauge needle in the study. In this regard, the highviscosity and sticky character of the placebo formulation preventedquantitative transfer of capsule contents into the syringe barrel.

Injectability of the placebo formulations at room temperature was onlyachieved using an 18 gauge needle at the slowest crosshead speed of 150mm/min. At 37° C., the formulation is less viscous and injectability wasachieved with all three samples using the 18 gauge needle at a speed of150 mm/min, and with two of the three samples using an 18 gauge needleat a speed of 550 mm/min. Either load failures of mechanical failuresoccurred at both test temperatures, and at all three crosshead speedswith the 21, 25 and 27 gauge needles.

The following information was considered in interpreting the outcome ofeach test. Single use disposable syringes are rated to withstand aninternal barrel pressure of 45 lb_(f)/in² for 30 seconds (correspondingto a pressure exerted on the plunger rod of 18.2 N). For 3 mL (ID=0.34in.) disposable syringe barrels, 1 lb_(f) applied to the plunger rodgenerates 11.0 lb_(f)/in² within the syringe barrel. The mean pinchforce (Palmer Pinch) exerted by healthy males is 23 to 23.4 lb_(f).

The following failure modes were used to assess injectability in thisstudy. Overall failure of the test was concluded upon failure of atleast one sample with a triplicate test set. A Plunger Barrel failureoccurs when excessive internal pressure causes the syringe barrel toflex, resulting in fluid bypassing the plunger stopper. This event isdetermined by observing the sample, or is evidenced by a declining loadforce profile in the Instron tracing. A Leur-Lok Coupling Failure occurswhen excessive internal pressure causes the needle to separate from thesyringe barrel. This failure event is determined by observing incompletesample delivery from the syringe, or is evidenced by a precipitous dropin the load force profile in the Instron tracing. An Excessive Forcefailure occurs when the force required to successfully deliver fluidfrom the syringe exceeds 23.4 lb_(f) (104 N), the average (Palmer) pinchforce of a healthy male. This event is evident from the Instron tracing.

Successful injection of placebo formulation required comparableperformance of all three test samples. The criterion for success was atleast 80% delivery of the initial pre-filled mass. In addition, theInstron tracing should display a consistent profile of force appliedduring plunger travel. Even in cases where the force profile remainedconsistent during the test and resulted in delivery of placebo mass fromthe syringe, a force greater than 62 N was required to achieve delivery.This magnitude of force generates a barrel pressure of 153 lb_(f)/in²,which is 340% of the pressure rated by the manufacturer.

These results of both the syringeability and injectability evaluationsdemonstrate the improbability of delivering an abuse-resistantcontrolled release formulation prepared according to the invention usingcommon hypodermic needles such as those available to drug abusers. Thisis thought to be due to a combination of limitations of suitable syringepressures, limitations of human strength and the highly viscous natureof the instant formulations.

Example 4d

The following in vitro Inhalation Abuse Resistance Evaluation wascarried out to characterize the ability of abuse-resistant formulationsprepared according to the present invention to resist inhalation-basedforms of abuse. More particularly, 2 different manufacturing lots ofabuse-resistant oxycodone oral dosage 40 mg strength forms produced withdifferent purity grades of the active agent (oxycodone) were used as theTest Capsules. OxyContin brand (oxycodone HCl controlled-release)Tablets, 40 mg strength (Lot W28A1, Purdue Pharma L.P.), (SR Control)were used as the commercial comparison.

The abuse-resistant oxycodone oral dosage forms used in this Example 4dwere prepared using the following raw materials: Oxycodone base,micronized (“OXY”), grade 2 (specified to contain not more than 0.25%(w/w) 14-hydroxycodeinone (14-HC)) or grade 1 (specified to contain notmore than 0.001% (w/w) 14-HC), both grades obtained from Noramco, Inc(Athens Ga.); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize #00 hard gelatin cap shells to produce the 40 mg dosage forms thatwere used as Test Capsules. The details of the formulations and thedosage forms containing the formulations of this Example 4d aredisclosed below in Table 50.

TABLE 50 OXY SAIB TA CAB IPM HEC SiO₂ BHT (total) 5.13 40.98 27.32 4.7414.23 5.69 1.9 0.02 (wt %) 40.0 319.6 213.1 37.0 111.0 44.4 14.8 0.16780.0 (mg)

The in vitro Inhalation Abuse Resistance Evaluation used the followingTest Capsules: three 40 mg dosage forms (n=3), containing grade 2oxycodone (OXY1); three 40 mg dosage forms (n=3), containing grade 1oxycodone (OXY2). The commercial comparison was against three 40 mg SRControl tablets (n=3).

A volatilization study was conducted to evaluate the potential for abuseof the Test Capsules by inhalation. Initially, thermal gravimetricanalysis was used to measure the weight loss of oxycodone base andoxycodone HCl in order to determine the correct temperature to conductthe volatilization study. Oxycodone base was subjected to increasingtemperature conditions (30 to 350° C.) at a ramping rate of 20° C./min.Vaporization occurred above 200° C. and was complete at 310° C.Vaporization of oxycodone HCl (28 to 400° C.) was analogous to that ofthe free base up to approximately 300° C. after which significantdecomposition of the salt form occurred. Based on these observations, atemperature of 280° C. was selected for this study. This temperature isabove the melting point of oxycodone (to ensure adequate drugvaporization) and below 300° C. (to limit decomposition of the saltform). A maximum exposure time of 10 minutes was selected based onpre-test observations that little additional oxycodone was recoveredbeyond that time point.

A volatilization system was designed to control the temperature appliedto the test samples. The system was constructed from an aluminum block,with temperature monitoring thermocouple, mounted to a hot plate. Eachaluminum block contains four holes for positioning of glass sampledishes. Each sample dish was capped with a pre-chilled aluminum coverthat held a frozen gel pack on top to facilitate condensation ofvolatilized oxycodone. Three dishes contained test samples in eachtrial, while the fourth served as a blank control. The two lots of TestCapsules and the single lot of SR Control tablets were evaluated intriplicate. Each Test Capsule was cut open and the liquid contentssqueezed into a sample dish, and each SR Control tablet was ground witha mortar and pestle and then transferred to a sample dish. The aluminumblock was stabilized at 280° C. prior to initiating the study. Thecovers were swabbed for oxycodone at 3, 5 and 10 minutes, and thesamples were analyzed using HPLC. The results of the volatilizationstudy were as follows: average oxycodone recoveries followingvolatilization at 280° C. (data in the form of mean oxycodone recoveredwith standard deviation (SD), reported as a % of initial dose): TestCapsules=2% (0.8) at 3 minutes; 4% (2.1) at 5 minutes; and 12% (2.1) at10 minutes. SR Control tablets=12% (2) at 3 minutes; 11% (2) at 5minutes; and 10% (2) at 10 minutes. These data are depicted in FIG. 19.

As can be seen by these results, volatilization of three SR Controltablets at 280° C. for 3 minutes resulted in an average oxycodonerelease of 12% of total drug mass; while volatilization of six TestCapsules tablets at 280° C. for 3 minutes only resulted in an averageoxycodone release of 2% of total drug mass. However, after 10 minutes,an approximately equal amount of oxycodone had volatilized from eachformulation (10% compared with 12% release). Observations during thetesting noted that vaporization of oxycodone from the Test Capsules wasaccompanied by liberation of smoke which is likely to be unpleasant(based upon volatilization of placebo Test Capsule formulations thatresulted in generation of pungent, acrid white smoke that was found toirritate the respiratory tract and throat when inhaled). Vaporization ofoxycodone from the SR Control tablets exhibited significant charring.The low level of oxycodone liberated from the Test Capsules upon initialheating in this volatilization study, accompanied by the generation ofan unpleasant smoke suggest that the abuse-resistant dosage forms of thepresent invention are likely to discourage abuse by inhalation.

Example 4e

The following in vitro Abuse Resistance Evaluation was carried out tocharacterize the in vitro abuse resistance performance of oxycodone oraldosage forms prepared according to the present invention. Moreparticularly, abuse-resistant oxycodone oral dosage forms across a rangeof formulations were assessed for resistance to extraction in an ethanolsolution. The abuse-resistant oxycodone oral dosage forms used in thisExample 4e were prepared using the following raw materials: Oxycodonebase, micronized (“OXY”); Isopropyl Myristate, NF (“IPM”); Colloidalsilicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyltoluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose AcetateIsobutyrate (Eastman Chemicals), (“SAM”); Triacetin USP (“TA”); SodiumLauryl Sulfate (“SLS”); Labrafil M2125 CS (“LAB”); Gelucire 44/14(Gattefosse) (“GEL”); and Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”). The formulations wereproduced using the commercial-scale manufacturing methods (ProcessSchemes 4 or 5 as described above) and then filled into size #00 hardgelatin cap shells to produce 80 mg dosage forms that were used as TestCapsules. The details of the formulations and the dosage formscontaining the formulations of this Example 4e are disclosed below inTable 51.

TABLE 51 OXY SAIB TA CAB IPM HEC SiO2 BHT SLS LAB GEL (Total) OXY1 80.0281.4 208.4 42.0 112.0 42.0 14.0 0.2 — — — 780 (mg) 10.26 36.08 26.725.38 14.36 5.38 1.79 0.02 — — — (wt %) OXY2 80.0 297.5 198.4 42.0 105.042.0 14.0 0.2 1.0 — — 780 (mg) 10.26 38.14 25.43 5.38 13.46 5.38 1.790.02 0.13 — — (wt %) OXY3 80.0 285.5 190.3 42.0 105.0 42.0 14.0 0.2 —21.0 — 780 (mg) 10.26 36.60 24.40 5.38 13.46 5.38 1.79 0.02 — 2.69 — (wt%) OXY4 80.0 280.4 207.7 36.7 119.0 42.0 14.0 0.2 — — — 780 (mg) 10.2635.95 26.63 4.71 15.26 5.38 1.79 0.02 — — — (wt %) OXY5 80.0 281.0 200.842.0 119.0 42.0 14.0 0.2 1.0 — — 780 (mg) 10.26 36.03 25.74 5.38 15.265.38 1.79 0.02 0.13 — — (wt %) OXY6 80.0 286.6 191.0 36.7 112.0 42.014.0 0.2 — 17.5 — 780 (mg) 10.26 36.74 24.49 4.71 14.36 5.38 1.79 0.02 —2.24 — (wt %) OXY7 80.0 284.4 210.7 42.0 112.0 21.0 15.8 0.2 — — 14.0780 (mg) 10.26 36.46 27.01 5.38 14.36 2.69 2.02 0.02 — — 1.79 (wt %)OXY8 80.0 282.4 209.2 38.5 112.0 42.0 15.8 0.2 — — — 780 (mg) 10.2636.21 26.82 4.94 14.36 5.38 2.02 0.02 — — — (wt %) OXY9 80.0 285.9 204.338.5 112.0 42.0 15.8 0.2 1.4 — — 780 (mg) 10.26 36.66 26.19 4.94 14.365.38 2.02 0.02 0.18 — — (wt %)

The in vitro Abuse Resistance Evaluation used the following TestCapsules: six (n=6) each of formulations OXY1-OXY9.

The ethanol solution extraction study was carried out substantially thesame as in Example 4a above, using the same apparatus, reagents andmethods described above, with the following exceptions: the extractionsolution was 60 mL of 80 proof ethanol (40%); and sampling was conductedat time=0.5 hour, 1, 2 and 3 hours. The results of the extraction studyare provided below in Table 52.

TABLE 52 Amount of Oxycodone Extracted in 80 Proof Ethanol (% of dose)Time (hr.) 0.5 1 2 3 OXY1 Mean 7 16 25 32 Std Dev. 1 4 6 8 OXY2 Mean 818 28 35 Std Dev. 2 3 4 5 OXY3 Mean 8 14 21 27 Std Dev. 2 2 5 6 OXY4Mean 12 18 26 32 Std Dev. 1 2 3 3 OXY5 Mean 11 16 24 30 Std Dev. 2 3 3 4OXY6 Mean 8 11 14 17 Std Dev. 1 1 1 2 OXY7 Mean 9 15 — 30 Std Dev. 1 2 —2 OXY8 Mean 12 18 — 32 Std Dev. 1 2 — 3 OXY9 Mean 12 18 — 33 1 2 — 3

Example 4f

The following in vitro Abuse Resistance Evaluation was carried out tocharacterize the in vitro abuse resistance performance of hydromorphoneoral dosage forms prepared according to the present invention. Moreparticularly, abuse-resistant hydromorphone oral dosage forms across arange of strengths (8 mg and 16 mg strengths) and across a range offormulations were assessed for resistance to extraction in an ethanolsolution. The abuse-resistant hydromorphone oral dosage forms used inthis Example 4f were prepared using the following raw materials:Hydromorphone HCl (“HMH”); Isopropyl Myristate, NF (“IPM”); Colloidalsilicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyltoluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose AcetateIsobutyrate (Eastman Chemicals), (“SAM”); Triacetin USP (“TA”); LabrafilM2125 CS (“LAB”); and Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”). The formulations wereproduced using the GMP manufacturing method of Example 1d above (ProcessScheme 8) and then filled into either size #1 (HMH1) or #2 (HMH2-4) gelcap shells to produce 8 and 16 mg dosage forms that were used as TestCapsules. The details of the formulations used in this Example 4f aredisclosed below in Table 53.

TABLE 53 Formula: HMH SAIB TA CAB IPM HEC SiO₂ BHT LAB Total HMH1 16.0108.6 80.4 15.5 41.4 7.8 5.2 0.1 — 275.0 (mg) 5.82 39.49 29.5 5.65 15.075.65 1.88 0.02 — (wt %) HMH2 16.0 104.1 77.1 15.5 41.4 15.5 5.2 0.1 —275.0 (mg) 5.82 37.86 28.05 5.65 15.07 5.65 1.88 0.02 — (wt %) HMH3 16.0101.1 74.9 15.5 38.9 15.5 5.2 0.1 7.8 275.0 (mg) 5.82 36.78 27.24 5.6514.13 5.65 1.88 0.02 2.83 (wt %) HMH4 8.0 29.8 19.9 3.6 10.8 4.3 1.4 0.12.2 80.0 (mg) 10.00 37.25 24.83 4.50 13.50 5.40 1.80 0.02 2.70 (wt %)

The in vitro Abuse Resistance Evaluation used the following TestCapsules: six 16 mg dosage forms, formulation HMH1 (n=6); six 16 mgdosage forms, formulation HMH2 (n=6); six 16 mg dosage forms,formulation HMH3 (n=6); and six 8 mg dosage forms, formulation HMH4(n=6).

The ethanol solution extraction study was carried out substantially thesame as in Example 4a above, using the same apparatus, reagents andmethods described above, with the following exceptions: the extractionsolution was 60 mL of 80 proof ethanol (40%); and sampling was conductedat time=0.5 hour, 1, 2 and 3 hours. The results of the extraction studyare provided below in Table 54.

TABLE 54 Amount of Hydromorphone Extracted in 80 Proof Ethanol (% ofdose) Time (hr.) 0.5 1 2 3 HMH1 Mean 3 5 8 10 Std Dev. 0 1 1 1 HMH2 Mean7 12 18 22 Std Dev. 0 1 3 4 HMH3 Mean 6 9 14 20 Std Dev. 2 1 2 2 HMH4Mean 9 13 20 27 Std Dev. 1 2 4 6

Example 4g

The following in vitro Abuse Resistance Evaluation was carried out tocharacterize the in vitro abuse resistance performance of hydrocodoneoral dosage forms prepared according to the present invention. Moreparticularly, abuse-resistant hydrocodone oral dosage forms across arange of strengths (15 mg and 75 mg strengths) and across a range offormulations were assessed for resistance to extraction in an ethanolsolution. The abuse-resistant hydrocodone oral dosage forms used in thisExample 4g were prepared using the following raw materials: HydrocodoneBitartrate (“HCB”); Isopropyl Myristate, NF (“IPM”); Colloidal silicondioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF(“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate(Eastman Chemicals), (“SAM”); Triacetin USP (“TA”); Gelucire 44/14(Gattefosse) (“GEL”); and Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”). The formulations wereproduced using the GMP manufacturing method of Example 1e above (ProcessScheme 9) and then filled into size #3 gel cap shells to produce thedosage forms that were used as Test Capsules. The details of theformulations and the dosage forms containing the formulations of thisExample 4g are disclosed below in Table 55.

TABLE 55 Formula HCB SAIB TA CAB IPM HEC SiO₂ BHT GEL Total # (mg) (mg)(mg) (mg) (mg) (mg) (mg) (02 mg) (mg) (mg) HCB1 15.0 41.8 27.8 5.2 14.242.8 1.9 0.1 1.1 110.0 (mg) 13.64 37.97 25.31 4.75 12.95 2.59 1.73 0.021.04 (wt %) HCB2 75.0 208.8 139.2 26.1 71.2 14.2 9.5 0.11 5.7 550.0 (mg)13.63 37.96 25.31 4.75 12.95 2.58 1.73 0.02 1.04 (wt %)

The in vitro Abuse Resistance Evaluation used the following TestCapsules: six 15 mg dosage forms, formulation HCB1 (n=6); and six 75 mgdosage forms, formulation HCB2 (n=6).

The ethanol solution extraction study was carried out substantially thesame as in Example 4a above, using the same apparatus, reagents andmethods described above, with the following exceptions: the extractionsolution was 60 mL of 80 proof ethanol (40%); and sampling was conductedat time=0.5 hour, 1 and 3 hours. The results of the extraction study areprovided below in Table 56.

TABLE 56 Amount of Hydrocodone Extracted in 80 Proof Ethanol (% of dose)Time (hr.) 0.5 1 3 HCB1 Mean 9 12 20 Std Dev. 1 1 2 HCB2 Mean 3 5 12 StdDev. 1 2 2

Example 4h

The following in vitro Abuse Resistance Evaluation was carried out tocharacterize the in vitro abuse resistance performance of oxymorphoneoral dosage forms prepared according to the present invention. Moreparticularly, abuse-resistant oxymorphone oral dosage forms across arange of formulations were assessed for resistance to extraction in anethanol solution. The abuse-resistant oxymorphone oral dosage forms usedin this Example 4h were prepared using the following raw materials:oxymorphone HCl (“OMH”); Isopropyl Myristate, NF (“IPM”); Colloidalsilicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyltoluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose AcetateIsobutyrate (Eastman Chemicals), (“SAM”); Triacetin USP (“TA”);Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (EastmanChemicals) (“CAB”); and Gelucire 44/14 (Gattefosse) (“GEL”). Theformulations were produced using the lab-scale manufacturing processdescribed in Example 3f above and then filled into size #1 gel capsulesto produce the dosage forms that were used as Test Capsules. The detailsof the formulations and the dosage forms containing the formulations ofthis Example 4h are disclosed below in Table 57.

TABLE 57 OMH SAIB TA CAB IPM HEC SiO₂ BHT GEL (Total) OMH1 40.00 226.38150.92 25.50 76.50 15.30 12.75 0.10 2.55 550 (mg) 7.27 41.16 27.44 4.6413.91 2.78 2.32 0.02 0.46 (wt %) OMH2 40.00 214.14 142.76 25.50 76.5035.70 7.65 0.10 7.65 550 (mg) 7.27 38.93 25.96 4.64 13.91 6.49 1.39 0.021.39 (wt %) OMH3 40.00 226.38 150.92 30.60 76.50 15.30 7.65 0.10 2.55550 (mg) 7.27 41.16 27.44 5.56 13.91 2.78 1.39 0.02 0.46 (wt %) OMH440.00 214.14 142.76 25.50 76.50 35.70 12.75 0.10 2.55 550 (mg) 7.2738.93 25.96 4.64 13.91 6.49 2.32 0.02 0.46 (wt %) OMH5 40.00 208.02138.68 30.60 76.50 35.70 12.75 0.10 7.65 550 (mg) 7.27 37.82 25.21 5.5613.91 6.49 2.32 0.02 1.39 (wt %) OMH6 40.00 214.14 142.76 30.60 76.5035.70 7.65 0.10 2.55 550 (mg) 7.27 38.93 25.96 5.56 13.91 6.49 1.39 0.020.46 (wt %) OMH7 40.00 220.26 146.84 30.60 76.50 15.30 12.75 0.10 7.65550 (mg) 7.27 40.05 26.70 5.56 13.91 2.78 2.32 0.02 1.39 (wt %) OMH840.00 226.38 150.92 25.50 76.50 15.30 7.65 0.10 7.65 550 (mg) 7.27 41.1627.44 4.64 13.91 2.78 1.39 0.02 1.39 (wt %) OMH9 40.00 218.73 145.8228.05 76.50 25.50 10.20 0.10 5.10 550 (mg) 7.27 39.77 26.51 5.10 13.914.64 1.85 0.02 0.93 (wt %)  OMH10 40.00 206.49 152.96 25.50 81.60 35.707.65 0.10 — 550 (mg) 7.27 37.54 27.81 4.64 14.84 6.49 1.39 0.02 — (wt %)

The in vitro Abuse Resistance Evaluation used the following TestCapsules: three each (n=3) of formulations OMH1-OMH10.

The ethanol solution extraction study was carried out substantially thesame as in Example 4a above, using the same apparatus, reagents andmethods described above, with the following exceptions: the extractionsolution was 60 mL of 80 proof ethanol (40%); and sampling was conductedat time=0.5 hour, 1 and 3 hours. The results of the extraction study areprovided below in Table 58.

TABLE 58 Amount of Oxymorphone Extracted in 80 Proof Ethanol (% of dose)Time (hr.) 0.5 1 3 OMH1 Mean 2 3 8 Std Dev. 1 1 1 OMH2 Mean 10 17 40 StdDev. 1 2 5 OMH3 Mean 3 4 14 Std Dev. 1 2 2 OMH4 Mean 3 5 13 Std Dev. 1 13 OMH5 Mean 5 9 24 Std Dev. 0 0 2 OMH6 Mean 2 4 10 Std Dev. 0 0 1 OMH7Mean 5 8 15 Std Dev. 1 1 1 OMH8 Mean 10 14 27 Std Dev. 2 2 4 OMH9 Mean 45 10 Std Dev. 1 1 1 OMH10 Mean 6 11 24 Std Dev. 4 6 9

Example 4i

The following in vitro Abuse Resistance Evaluation was carried out tocharacterize the in vitro abuse resistance performance of amphetamineoral dosage forms prepared according to the present invention. Moreparticularly, abuse-resistant amphetamine oral dosage forms across arange of formulations were assessed for resistance to extraction in anethanol solution. The abuse-resistant amphetamine oral dosage forms usedin this Example 4i were prepared using the following raw materials:d-Amphetamine Sulfate (Cambrex) (“AMP”); Isopropyl Myristate, NF(“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”);Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF(“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAM”);Triacetin USP (“TA”); Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”); CaprylocaproylPolyoxyglycerides (Gattefosse) (“CPG”); Gelucire 50/13 (Gattefosse)(“GEL”); and Polyethylene Glycol 8000 (Dow Chemical) (“PEG 8000”). Theformulations were produced using a GMP manufacturing process (ProcessScheme 6 as described in Example 1a above) and then filled into size #1gel capsules to produce the dosage forms that were used as TestCapsules. The details of the formulations and the dosage formscontaining the formulations of this Example 4i are disclosed below inTables 59 and 60.

TABLE 59 Formulation by Weight Percent (wt %) Component AMP1 AMP2 AMP3AMP 7.50 5.45 5.45 SAIB 36.52 36.24 35.16 TA 27.05 26.85 26.04 CAB 4.864.96 4.96 IPM 15.73 16.07 16.07 HEC 5.55 5.67 5.67 SiO₂ 1.85 1.89 1.89BHT 0.02 0.02 0.02 LAB 0.93 0 0 PEG 8000 0 2.84 0 GEL 0 0 4.73

TABLE 60 Formulation by Mass (mg) Component AMP1 AMP2 AMP3 AMP 15.0014.99 14.99 SAIB 73.04 99.66 96.69 TA 54.10 73.84 71.61 CAB 9.72 13.6413.64 IPM 31.46 44.19 44.19 HEC 11.10 15.93 15.59 SiO₂ 3.70 5.20 5.20BHT 0.04 0.06 0.06 LAB 1.86 0 0 PEG 8000 0 7.81 0 GEL 0 0 13.01 Total200.02 275.32 274.98

The in vitro Abuse Resistance Evaluation used the following TestCapsules: three (n=3) each of formulations AMP1-AMP3.

The ethanol solution extraction study was carried out substantially thesame as in Example 4a above, using the same apparatus, reagents andmethods described above, with the following exceptions: the extractionsolution was 60 mL of 80 proof ethanol (40%); and sampling was conductedat time=0.5 hour and 3 hours. The results of the extraction study areprovided below in Table 61.

TABLE 61 Amount of Amphetamine Extracted in 80 Proof Ethanol (% of dose)Time (hr.) 0.5 3 AMP1 Mean 23 59 Std Dev. 2 4 AMP2 Mean 8 27 Std Dev. 02 AMP3 Mean 12 39 Std Dev. 0 2

Example 4j

The following in vitro Abuse Resistance Evaluation was carried out tocharacterize the in vitro abuse resistance performance ofmethylphenidate oral dosage forms prepared according to the presentinvention. More particularly, abuse-resistant methylphenidate oraldosage forms across a range of formulations were assessed for resistanceto extraction in an ethanol solution. The abuse-resistantmethylphenidate oral dosage forms used in this Example 4j were preparedusing the following raw materials: methylphenidate (“MPH”); IsopropylMyristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp)(“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethylcellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals),(“SAM”); Triacetin USP (“TA”); Cellulose Acetate Butyrate, grade 381-20BP, ethanol washed (Eastman Chemicals) (“CAB”); Gelucire 50/13(Gattefosse) (“GEL”); and Miglyol 812 (“MIG”). The formulations wereproduced using the manufacturing process (Process Scheme 6) as describedin Example 1a above, and then filled into size #3 gelatin capsule shellsto produce the dosage forms that were used as Test Capsules. The detailsof the formulations and the dosage forms containing the formulations ofthis Example 4j are disclosed below in Tables 62 and 63.

TABLE 62 Formulation by Weight Percent (wt %) MPH1 MPH2 MPH3 MPH4 MPH5MPH6 Component 40 mg 48 mg 48 mg 48 mg 48 mg 48 mg MPH 20.00 20.00 20.0020.00 20.00 20.00 SAM 33.35 34.31 34.55 34.31 29.25 34.55 TA 22.23 22.8723.03 22.87 20.89 23.03 CAB 4.80 5.20 6.40 5.21 5.58 6.42 IPM 13.6012.80 12.80 12.80 — 12.80 MIG — — — — 16.0 — HEC 0.00 2.40 0.00 2.404.80 — SiO₂ 2.00 1.60 1.60 1.60 1.60 1.60 BHT 0.02 0.02 0.02 0.02 0.020.02 GEL 4.00 0.80 1.60 0.80 1.84 1.60

TABLE 63 Formulation by Mass (mg) MPH1 MPH2 MPH3 MPH4 MPH5 MPH6Component 40 mg 48 mg 48 mg 48 mg 48 mg 48 mg MPH 40.00 48.00 48.0048.00 48.00 48.00 SAM 66.70 82.34 82.92 82.30 70.20 82.90 TA 44.46 54.8955.27 54.90 50.10 55.30 CAB 9.60 12.48 15.36 12.50 13.40 15.40 IPM 27.2030.72 30.72 30.70 — 30.70 MIG — — — — 38.40 — HEC 0.00 5.76 0.00 5.8011.50 — SiO₂ 4.00 3.84 3.84 3.80 3.80 3.80 BHT 0.04 0.05 0.05 0.05 0.050.05 GEL 8.00 1.92 3.84 1.90 4.40 3.80 Total 200.00 240.00 240.00 240.00240.00 240.00

The in vitro Abuse Resistance Evaluation used the following TestCapsules: three (n=3) each of formulations MPH1-MPH6.

The ethanol solution extraction study was carried out substantially thesame as in Example 4a above, using the same apparatus, reagents andmethods described above, with the following exceptions: the extractionsolution was 60 mL of 80 proof ethanol (40%); and sampling was conductedat time=0.5 hr and 3 hours. The results of the extraction study areprovided below in Table 64.

TABLE 64 Amount of Methylphenidate Extracted in 80 Proof Ethanol (% ofdose) Time (hr.) 0.5 3 MPH1 Mean 18.4 63.0 Std Dev. 0.9 0.9 MPH2 Mean7.2 25.7 Std Dev. 0.5 1.7 MPH3 Mean 6.1 22.9 Std Dev. 0.6 1.3 MPH4 Mean10 32 Std Dev. 1 3 MPH5 Mean 10 40 Std Dev. 1 2 MPH6 Mean 11 43 Std Dev.2 4

Example 5 Analysis of Formulations

(Formulation Viscosity Testing Procedures)

In order to assess the viscosity of formulations prepared in accordancewith the present invention, the following viscosity tests weredeveloped. Both standard and dynamic viscosity measurements may beobtained using these tests. The viscosity testing apparatus used in themethods described in this Example 5 are Brookfield Digital Rheometers.The two specific models used are the following: JPII, Model HBDV-III+CPwith a programmable/digital Controller Model 9112; and JPI, ModelLVDV-III+CP, with an Immersion Circulator Model 1122S. For bothrheometer models the CPE Spindle 52 was used. For Dynamic Rheology, thedynamic rheology of the formulations can be measured using an Anton PaarPhysica MCR301 rheometer (Anton Paar USA, Ashland, Va.) that is equippedwith temperature and oscillatory strain control modules.

Sample formulations can be presented in two different formats for theviscosity testing methods, either as bulk formulation or as singledosage forms (e.g., gelatin capsules). For bulk formulation testing, 0.5mL of the formulation is injected directly into the rheometer cup. Whentesting dosage forms, two gelatin capsules are needed for eachmeasurement. The gelatin capsules are opened using a razor blade and aclean cutting surface. The contents are then squeezed out and placed inthe rheometer cup.

Typical temperature conditions for the viscosity testing methods are 37°C. for most single point measurements, and 30° C., 40° C., 50° C., and60° C. for temperature profiles. For each sample two different shearrates measured: 1^(st)—low shear, an rpm setting is selected to providea torque value between 10-15%; and 2^(nd)—high shear, an rpm setting isselected to give a torque value between 20-90%

Data collection of the viscosity measurements is carried out usingstandard techniques. For example, the Brookfield Digital Rheometer datareport screen automatically displays the rotational speed, spindlenumber, torque value (%), and the viscosity for manual recording.

Finally, complex viscosity of formulation samples can be measured usingvarying oscillatory strain in the linear viscoelastic regime. Here, theintrinsic complex viscosity of a sample formulation at rest can beobtained based on a mathematical curve fit of empirical data points. Theadvantage of the dynamic oscillatory experiment is that it probes thesample formulation material without destroying the material'smicrostructure.

Example 6 In Vitro/In Vivo Correlation (IVIVC) Analysis of Formulations

The concept of in vitro/in vivo correlation (IVIVC) determination for anoral extended (controlled, sustained) release dosage forms is awell-known tool used by pharmaceutical scientists, allowing for theprediction of expected bioavailability and other pharmacologicalperformance characteristics from in vitro dissolution profilecharacteristics. Information and guidance regarding IVIVC determinationcan be found on the US FDA website and in other pharmacologicalreference sites. In order to assess and characterize the abuse-resistantdosage forms prepared in accordance with the present invention, thefollowing IVIVC analyses were carried out.

Example 6a

The following IVIVC analysis was used to establish the correlationbetween the in vitro controlled release profile of candidateformulations obtained using the second dissolution method (Method 2)described above in Example 3 (that was optimized to assess thecontrolled release performance of the controlled release dosage forms ofthe present invention) and the in vivo blood concentration data obtainedin the pharmacokinetic human clinical trails described herein below viadeveloping a transformation function according to FDA Guideline forExtended Release (ER) dosage forms.

More particularly, a predictive mathematical model describing therelationship between the rate or extent of active agent dissolutionobserved in the in vitro dissolution testing described in Example 3above, and the actual in vivo pharmacokinetic performance observed(measured plasma drug concentration or amount of active agent absorbedupon administration to human subjects, for example in Examples 7 and 8below) was developed for an abuse-resistant oxycodone oral dosage formprepared in accordance with the present invention. In particular, thefollowing raw materials were used to create formulations for use in thestudies: Oxycodone base, micronized (“OXY”); Isopropyl Myristate, NF(“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”);Butylated hydroxyl toluene, NF (“BHT”); Hydroxyethyl cellulose, NF(“HEC”); Sucrose Acetate Isobutyrate (Eastman Chemicals), (“SAM”);Triacetin USP (“TA”); and Cellulose Acetate Butyrate, grade 381-20 BP,ethanol washed (Eastman Chemicals) (“CAB”). The formulations were filledinto gel caps to provide suitable dosage forms (Test Capsules).

Ideally, plasma concentrations of oxycodone after administration of theTest Capsules would have been obtained in one crossover study in onepanel of volunteers. However, as the data were obtained from differentstudies, all pharmacokinetic, deconvolution, and convolution analyseswere done using the mean plasma concentration data from the respectivestudies. The Test Capsule in vitro data were fit to the Weibullfunction,

${\%\mspace{14mu}{Dissolved}} = {100\% \times \left( {1 - {\mathbb{e}}^{- {(\frac{t}{\tau})}^{\beta}}} \right)}$

where τ is the time required for 62.5% of the dose to dissolve and β isthe slope parameter, which was the simplest model that was consistentwith the dissolution for the extremes in data for slow and fastdissoluting lots.

The mean plasma concentration-time data were consistent with atwo-compartment model with first-order absorption and elimination. Themodel was parameterized in terms of the absorption rate constant, K01,the elimination rate constant, K10, the distribution rate constants, K12and K21, and the volume of the central compartment (Compartment 1),Vc/F, □ where F is the bioavailability.

The parameters are derived from the secondary parameters, with theparameters “A” and “B” normalized to dose. The mean oxycodone plasmaconcentration-time data for the Test Capsule lots were deconvolutedusing the parameters estimated from the solution to obtain estimates ofthe in vivo release rates.

This analysis indicated that dissolution profiles for the Test Capsulelots that have a value of τ in the Weibull function ranging from 6 to 14h should provide equivalent in vivo plasma concentration-time profiles.Although the dissolution profile appears to slow over time, there is noapparent effect on in vivo bioavailability. In particular, the observedvalues of τ in the Weibull function (taken over the course of more thana year) were 6.09±0.12; 10.1±0.08; 12.8±0.19; 11.6±0.11; and 14.1±0.21.

Example 6b

The following analysis was used to establish the correlation between thein vitro controlled release profile of d-amphetamine from candidateabuse-resistant formulations, and in vivo blood concentration dataobtained in a pharmacokinetic human clinical trial described hereinbelow, via developing a transformation between the cumulative percent ofdose input into the systemic circulation in vivo (cumulative input) andthe cumulative percent of dose released in vitro (cumulative release).

Given human plasma concentration-time profiles of d-amphetamine derivedfrom oral dosing of abuse-resistant formulations prepared in accordancewith the present invention, cumulative input profiles can be obtainedthrough deconvolution. This necessitates having the unit impulseresponse function (UIR), which can be derived from a compartmentalpharmacokinetic analysis of human concentration-time data followingintravenous bolus dosing of d-amphetamine. Such data were obtained fromthe open literature:UIR=(Ae ^(−α) t+Be ^(−βt))/Dose_(iv)

where A=98.3±6.01, B=28.2±0.56, α=9.65±0.64, and β=6.31×10⁻²±3.78×10⁻³.

Deconvolution of the mean plasma profiles for three abuse-resistantamphetamine oral dosage forms was done in WinNonLin 5.2 (PharsightCorp., Mountain View, Calif.) to give values of the cumulative percentof dose absorbed in vivo. Values of the cumulative percent of dosereleased in vitro were measured using the second dissolution method atthe same times as the human concentration-time profiles. By plottingrelease in vitro against input in vivo, a transformation could be foundby least squares fitting of cubic polynomials. For example,y=ax ³ −bx ² +cx+d

where y is % release in vitro, x is % input in vivo, and a=2×10⁻⁴,b=2.54×10⁻², c=1.53 and d=36. Other functional forms providing a goodfit could be found. Having such a transformation, one can calculate thein vitro release profile required to produce a desiredconcentration-time profile in vivo.

In addition, by inverting the transformation, either analytically ornumerically, one can calculate input in vivo from release in vitro, andthen convolve the input with the UIR to predict the humanconcentration-time profile for d-amphetamine obtained from a particularin vitro release profile.

Example 7 In Vivo Analysis of Formulations

(Human Clinical Trials, Pharmacokinetic Studies)

In order to assess the in vivo controlled release performance ofabuse-resistant oxycodone oral dosage forms prepared in accordance withthe present invention, the following human clinical trails were carriedout. In all studies described below, plasma samples were analyzed foroxycodone, noroxycodone, and oxymorphone by CEDRA Corporation using avalidated LC-MS-MS procedure. The method was validated for a range of0.250 to 125 ng/mL for oxycodone, 0.500 to 250 ng/mL for noroxycodoneand 0.0500 to 25.0 ng/mL for oxymorphone. Data were analyzed bynoncompartmental methods in WinNonlin. Concentration-time data that werebelow the limit of quantification (BLQ) were treated as zero (0.00ng/mL) in the data summarization and descriptive statistics. In thepharmacokinetic analyses, BLQ concentrations were treated as zero fromtime-zero up to the time at which the first quantifiable concentrationwas observed; embedded and/or terminal BLQ concentrations were treatedas “missing”.

The abuse-resistant oxycodone oral dosage forms used in the studies wereprepared using the following raw materials: Oxycodone base, micronized(“OXY”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize 00 white opaque gel cap shells to produce 5, 10, 20, 30 and 40 mgdosage forms that were used as Test Capsules. The details of theformulations and the dosage forms containing the formulations used inthe studies of Examples 7a-7f are disclosed below in Tables 65 and 66.

TABLE 65 OXY SAIB TA CAB IPM HEC SiO₂ BHT (wt %) (wt %) (wt %) (wt %)(wt %) (wt %) (wt %) (wt %) 5.13 40.98 27.32 4.74 14.23 5.69 1.9 0.02

TABLE 66 Capsule OXY SAIB TA CAB IPM HEC SiO₂ BHT Total Strength (mg)(mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg)  5 mg 5.0 40.0 26.6 4.6 13.9 5.51.8 0.02 97.5 10 mg 10.0 79.9 53.3 9.2 27.7 11.1 3.7 0.04 195.0 20 mg20.0 159.8 106.5 18.5 55.5 22.2 7.4 0.08 390.0 30 mg 30.0 239.7 159.827.8 83.2 33.3 11.1 0.12 585.0 40 mg 40.0 319.6 213.1 37.0 111.0 44.414.8 0.16 780.0

Example 7a

The following human clinical trial study was a single-center, two-waycrossover registration PK study to demonstrate the bioequivalence of twoabuse-resistant oxycodone formulations prepared in accordance with thepresent invention and used for clinical trial supplies, that is,formulations produced using Process Scheme 4 method (see Example 2)versus formulations made using the Process Scheme 5 method (see Example2). This study was conducted in 48 healthy adult male and femalevolunteers (fed state). The formulations were provided as 40 mg dosageform Test Capsules and prepared as discussed above. A single dose ofeach of the two formulations was administered separated by 96 hours.Subjects were administered naltrexone blockade to prevent opioid-relatedadverse events.

Mean linear plasma concentration-time curves of oxycodone in the studyare shown in FIG. 19. The C_(max) and T_(max) values, based on meanoxycodone plasma concentration-time values, are presented below in Table67, while the mean (SD) oxycodone PK parameters from noncompartmentalanalysis of individual data in the study are presented below in Table68.

TABLE 67 Mfr. Process Scheme 4 Mfr. Process Scheme 5 Parameter (40 mgOxycodone) (40 mg Oxycodone) T_(max) (hr) 4.67 4.67 C_(max) (ng/mL) 39.737.5

TABLE 68 Mfr. Process Scheme 4 Mfr. Process Scheme 5 (40 mg Oxycodone)(40 mg Oxycodone) Parameter Mean (SD) Mean (SD) T_(max) (hr) 5.34 (2.19)5.76 (2.72) C_(max) (ng/mL) 46.4 (14.4) 45.0 (17.8) AUC_(last) (hr *ng/mL) 533.6 (168.5) 545.8 (161.2) AUC_(inf) (hr * ng/mL) 540.4 (169.6)561.2 (162.0)

As can be seen from the data, a statistical analysis of thelog-transformed C_(max) and AUC parameters demonstrated that theformulations manufactured by Process Schemes 4 and 5 were bioequivalent.

Example 7b

This next human clinical trial study was a single-center, three-waycrossover, food effect, PK study to determine the rate and extent ofabsorption of 40 mg oxycodone base in abuse-resistant oral dosage formswhen administered in a fasted state, after consumption of a low fatmeal, and after consumption of a high fat meal. This study was conductedin 48 healthy, adult male and female volunteers. Subjects wereadministered naltrexone blockade to prevent opioid-related adverseevents. Forty-six subjects received all three doses of study dosageforms. Mean linear and semi-logarithmic oxycodone plasmaconcentration-time curves from the study are shown in FIG. 21

The C_(max) and T_(max) values, based on mean oxycodone plasmaconcentration-time values, are presented below in Table 69, and meanoxycodone PK parameters from noncompartmental analysis of individualdata in the study are presented below in Table 70.

TABLE 69 40 mg OXY 40 mg OXY 40 mg OXY Parameter (Fasted) (Low FatBreakfast) (High Fat Breakfast) T_(max) (hr) 3.33 4.67 6.50 C_(max)(ng/mL) 22.2 33.5 38.6

TABLE 70 40 mg OXY 40 mg OXY 40 mg OXY (Low Fat (High Fat (Fasted)Breakfast) Breakfast) Parameter Mean (SD) Mean (SD) Mean (SD) T_(max)(hr) 3.99 (1.80)  4.10 (1.24)  5.72 (2.03)  C_(max) (ng/mL) 25.8 (10.3) 38.7 (16.2)  50.6 (24.4)  AUC_(0-t) 429.3 (162.1) 499.0 (173.0) 549.0(178.9) (hr*ng/mL) AUC_(inf) 515.5 (129.6) 545.2 (170.2) 602.1 (148.9)(hr*ng/mL)

Log-transformed parameters were calculated for maximum exposure(C_(max)) and total exposure (AUC_(last) and AUC_(inf)) and used in thestatistical analysis. The 90% confidence intervals for the treatmentratios (test-to-reference) of the three parameters using thelog-transformed data and the two one-sided t-tests procedure indicatedthat oxycodone exposure parameters for either low fat or high fat fedconditions were not within the 80-125% limits of the fasted condition.Therefore, food has a significant effect on both the rate and extent ofabsorption of oxycodone from the study abuse-resistant oral dosageforms; oral bioavailability is increased under fed conditions relativeto administration of dosage forms in the fasted state. There was nosignificant difference in the extent of exposure resulting from eitherthe low or high fed breakfast.

Example 7c

The following human clinical trial study was a single-center, four-waycrossover PK study to demonstrate the dose proportionality of 5, 10, 20,and 40 mg abuse-resistant oral dosage forms produced according to thepresent invention and administered under single dose conditions. Thisstudy was conducted in 48 healthy adult male and female volunteers (fedstate). Subjects were administered naltrexone blockade to preventopioid-related adverse events. Forty-six subjects received all fourdoses of study dosage forms. The mean linear and semi-logarithmicoxycodone plasma concentration-time curves obtained in the study areshown in FIG. 22. The C_(max) and T_(max) values from this Example 7cstudy, based on mean oxycodone plasma concentration-time values, arepresented below in Table 71. The mean oxycodone PK parameters fromnoncompartmental analysis of individual data in this Example 7c studyare presented in Table 72 and depicted in FIG. 23. As can be seen, thestatistical analysis indicated the study dosage forms are doseproportional over the entire range of doses.

TABLE 71 Parameter 5 mg OXY 10 mg OXY 20 mg OXY 40 mg OXY T_(max) (hr)4.33 4.67 4.50 4.67 C_(max) (ng/mL) 4.60 9.59 18.2 39.0

TABLE 72 5 mg OXY 10 mg OXY 20 mg OXY 40 mg OXY Parameter Mean (SD) Mean(SD) Mean (SD) Mean (SD) T_(max) (hr) 3.92 (1.08) 4.06 (1.09) 5.11(2.08) 5.49 (2.55) C_(max) (ng/mL) 5.16 (1.45) 10.9 (4.17) 21.3 (8.45)47.5 (23.7) AUC_(last) (hr*ng/mL) 58.90 (17.09) 125.4 (38.82) 264.3(75.58) 546.4 (166.4) AUC_(inf) (hr*ng/mL) 74.19 (15.78) 143.0 (38.04)292.5 (72.58) 577.9 (162.3)

Example 7d

The following human clinical trial study was a single-center, steadystate PK study in which subjects received 30 minutes after the start ofa standardized breakfast study abuse-resistant oral dosage forms (TestCapsules containing oxycodone free base, 40 mg, “OXY”) BID for 5 days.Subjects were administered naltrexone blockade to prevent opioid-relatedadverse events. Thirty-six subjects were enrolled in this study, 22males and 14 females. Two females and one male did not complete thestudy; 33 subjects were enrolled in the PK analysis.

The C_(max) and T_(max) values from this Example 7d study, based on meanoxycodone plasma concentration-time values, are presented below in Table73 and mean oxycodone PK parameters from noncompartmental analysis ofindividual data in this study are presented below in Table 74.

TABLE 73 Parameter Day 1 Day 5 T_(max) (hr) 4.75 4.50 C_(max) 38.5 58.7ng/mL)

TABLE 74 Day 1 Day 5 OXY Capsules, 40 mg OXY Capsules, 40 mg Parameter nMean SD CV % n Mean SD CV % T_(max) (hr) 33 5.51 2.11 38.29 33 4.34 1.4733.79 C_(max) (ng/mL) 33 44.6 17.8 39.90 33 64.4 26.3 40.77 T_(min) (hr)• • • • 33 9.15 4.98 54.43 C_(min) (ng/mL) • • • • 33 25.6 7.10 27.71AUC_(0-τ) (hr*ng/mL) • • • • 33 510.2 156.6 30.70 AUC₀₋₁₂ (hr*ng/mL) 33307.9 108.8 35.35 . . . . AUC₀₋₂₄ (hr*ng/mL) • • • • 33 738.5 212.128.72 AUC₀₋₃₆ (hr*ng/mL) • • • • 32 833.4 234.0 28.07 AUC₀₋₄₈ (hr*ng/mL)• • • • 32 868.1 240.9 27.75 AUC_(last) (hr*ng/mL) 33 307.9 108.9 35.3633 887.2 261.0 29.42 AUC_(inf) (hr*ng/mL) • • • • 30 908.5 256.7 28.26AUC_(Extrap) (%) • • • • 30 1.41 1.75 124.47 λ_(z) (hr⁻¹) • • • • 300.0790 0.0368 46.56 T_(1/)2 (hr) • • • • 30 11.28 6.27 55.56 T_(last)(hr) 33 12.00 0.02 0.13 33 68.73 30.04 43.71 C_(last) (ng/mL) 33 20.05.31 26.61 33 0.821 0.641 78.15 Fluctuation (%) • • • • 33 87.91 33.3037.88 Accumulation¹ • • • • 33 1.75 0.48 27.55 Note: Full precision dataused in pharmacokinetic analysis. ¹Accumulation = AUC_(0-τ) (Day5)/AUC₀₋₁₂ (Day 1).

In this study, a significant gender effect was observed for C_(max) andT_(max) of oxycodone at steady state. However, a small number of femalescompleted the study relative to the number of males that completed thestudy. An ANOVA found that the power for the study was low. Areplacement steady state study is thus described below in Example 7e.Based upon a comparison of the trough (pre-dose) plasma concentrationsafter the first dose of the study dosage forms on Study Days 1, 2, 3, 4,and 5, steady-state concentrations of oxycodone were, on average,achieved on Day 2. After the administration of the 40 mg study dosageforms every 12 hours for five consecutive days, there was a significantincrease in peak and overall systemic exposure to oxycodone,noroxycodone, and oxymorphone relative to exposure after the first dose.Based on log-transformed AUC₀₋₁₂ values in the current study, percentratios (Day 5/Day 1) were 168.46% for oxycodone, 306.24% fornoroxycodone, and 192.33% for oxymorphone. Based on AUC_(0-τ) (Day5)/AUC₀₋₁₂(Day1) ratios for individual subjects, there is a 1.75-foldincrease in oxycodone exposure during a dosing regiment of the 40 mgstudy dosage forms every 12 hours over 5 consecutive days. Theaccumulation ratios for noroxycodone and oxymorphone are 3.22 and 2.00,respectively.

Example 7e

The following human clinical study was a single-center, steady state PKstudy in which subjects received the study abuse-resistant oral dosageforms (capsules containing oxycodone free base, 30 mg, “OXY TestCapsules” or OXY) administered BID. Subjects were administerednaltrexone blockade to prevent opioid-related adverse events. Inaddition, subjects received a meal prior to each dose of the study TestCapsules (OXY). 48 subjects were enrolled in this study, 28 males and 20females. Three subjects did not complete the study and three othersubjects experienced emesis; with the final result being that 42subjects completed the PK analysis (25 males and 17 females).

The C_(max) and T_(max) values from subjects (pooled male and female)receiving the Test Capsules (OXY), based on mean oxycodone plasmaconcentration-time values, are presented below in Table 75 and meanoxycodone PK parameters from noncompartmental analysis of individualdata are presented below in Table 76.

TABLE 75 Day 5 Day 5 Parameter Day 1 Day 5 (Male) (Female) T_(max) (hr)4.50 4.75 4.75 4.75 C_(max) (ng/mL) 27.2 43.9 39.0 51.1

TABLE 76 Day 1 Day 5 OXY Test Capsules OXY Test Capsules Parameter nMean SD CV % n Mean SD CV % T_(max) (hr) 42 5.04 1.69 33.44 42 4.11 1.2229.61 C_(max) (ng/mL) 42 31.6 11.3 35.89 42 49.6 17.8 35.96 C_(min)(ng/mL) • • • • 42 19.2 7.37 38.36 AUC_(0-τ) (hr*ng/mL) 42 218.2 63.9129.9 42 378.7 116.0 30.62 AUC₀₋₁₂ (hr*ng/mL) 42 218.2 63.91 29.9 42378.7 116.0 30.62 AUC_(last) (hr*ng/mL) • • • • 42 661.9 222.8 33.66AUC_(inf) (hr*ng/mL) • • • • 39 686.3 223.0 32.49 T_(1/2) (hr) • • • •39 12.37 9.35 75.64 C_(last) (ng/mL) 42 15.7 6.09 38.78 42 0.650 0.42265.00 Fluctuation (%) • • • • 42 97.21 31.95 32.87

Based upon a comparison of the trough (pre-dose) plasma concentrationsafter the first dose of the study Test Capsules on Study Days 1, 2, 3,4, and 5, steady-state concentrations of oxycodone were, on average,achieved on Day 2. After the administration of the 30 mg Test Capsulesevery 12 hours for five consecutive days, there was a significantincrease in peak and overall systemic exposure to oxycodone,noroxycodone, and oxymorphone relative to exposure after the first dose.

As a further analysis, an investigation into a possible effect of genderon the pharmacokinetic profile of the Test Capsules following a singledose of the Test Capsules, and a steady-state multiple dosing regimen ofthe Test Capsules administered BID for 5 days. The pharmacokineticparameters of oxycodone after a single dose of the Test Capsules arereported below in Table 77, and the pharmacokinetic parameters ofoxycodone on day 5 after multiple dose administration of the TestCapsules are reported below in Table 78. The mean data for the male andfemale test groups from this gender analysis are reported above in Table75.

TABLE 77 Day 1 Day 1 Male Female OXY Test Capsules OXY Test CapsulesParameter n Mean SD CV % n Mean SD CV % T_(max) (hr) 25 4.87 1.85 38.0217 5.30 1.43 26.89 C_(max) (ng/mL) 25 26.8 8.63 32.18 17 38.6 11.4 29.61AUC_(0-T) (hr*ng/mL) 25 196.0 56.27 28.71 17 250.9 61.75 24.61AUC_(last) (hr*ng/mL) 25 196.0 56.27 28.71 17 251.0 61.70 24.58 C_(last)(ng/mL) 25 14.2 5.36 37.62 17 17.9 6.61 36.96

TABLE 78 Day 5 Day 5 Male Female OXY Test Capsules OXY Test CapsulesParameter n Mean SD CV % n Mean SD CV % T_(max) (hr) 25 4.01 1.26 31.3017 4.25 1.18 27.75 C_(max) (ng/mL) 25 44.3 12.8 28.82 17 57.5 21.5 37.38AUC_(0-T) (hr*ng/ 25 358.0 101.6 28.38 17 409.3 131.6 32.15 mL)AUC_(last) (hr*ng/ 25 636.0 206.9 32.50 17 698.9 246.0 35.19 mL)AUC_(inf) (hr*ng/ 23 664.4 204.6 30.79 16 717.8 250.6 34.91 mL) C_(min)(ng/mL) 25 18.6 7.14 38.31 17 20.1 7.84 39.08 Fluctuation (%) 25 87.8025.56 29.12 17 111.05 35.97 32.39

As can be seen by these gender results, peak oxycodone concentrationsfor males were lower and occurred at earlier times relative to themaximum oxycodone concentrations for females. The higher oxycodoneplasma concentrations observed for females were also reflected in theAUC values.

Example 7f

The following human clinical study was a multicenter, randomized,double-blind, placebo-controlled, phase III study in patients withmoderate to severe chronic pain due to osteoarthritis of the hip orknee. The study evaluated the efficacy and safety of abuse-resistantoral dosage forms (capsules containing oxycodone base and preparedaccording to the present invention) relative to placebo over a 12-weekdouble-blind treatment period.

The study abuse-resistant oral dosage forms used in the studies wereprepared using the following raw materials: Oxycodone base, micronized(“OXY”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize 00 white opaque gel cap shells to produce 5, 10, 20, 30 and 40 mgdosage forms that were used as Test Capsules. The details of theformulations of this Example 7f are disclosed below in Tables 79 and 80.

TABLE 79 OXY SAIB TA CAB IPM HEC SiO₂ BHT (wt %) (wt %) (wt %) (wt %)(wt %) (wt %) (wt %) (wt %) 5.13 40.98 27.32 4.74 14.23 5.69 1.9 0.02

TABLE 80 Capsule OXY SAIB TA CAB IPM HEC SiO₂ BHT Total Strength (mg)(mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg)  5 mg 5.0 40.0 26.6 4.6 13.9 5.51.8 0.02 97.5 10 mg 10.0 79.9 53.3 9.2 27.7 11.1 3.7 0.04 195.0 20 mg20.0 159.8 106.5 18.5 55.5 22.2 7.4 0.08 390.0 30 mg 30.0 239.7 159.827.8 83.2 33.3 11.1 0.12 585.0 40 mg 40.0 319.6 213.1 37.0 111.0 44.414.8 0.16 780.0

For the study, patients meeting eligibility criteria entered a 2-weekopen-label titration phase in which all patients were administered thestudy abuse-resistant oral dosage form 5 mg BID titrated up to 20 mgBID. Patients able to tolerate the study abuse-resistant oral dosageform 20 mg BID were randomized in a 1:1 ratio to receive the studyabuse-resistant oral dosage form BID or placebo BID. A total of 558patients were enrolled into the open-label titration phase of the studyand a total of 412 patients were randomized. Dose adjustments wereallowed during the first four weeks of the double-blind treatmentperiod.

A patient entered the two week open-label titration period if the meanvalue of the diary pain intensity score (PI) over the last 2 days of thewashout period (Baseline PI) is 5; if IVRS diary compliance was ≧75%;and, if the patient continued to meet all inclusion/exclusion criteria.Patients were titrated from the study abuse-resistant oral dosage form 5mg BID to 20 mg BID over these 2 weeks.

At the end of the open-label titration period, a patient was enrolled inthe double-blind placebo-controlled study if the patient was able totolerate the study abuse-resistant oral dosage form 20 mg BID (nounacceptable adverse events) and if IVRS diary compliance was ≧75%. Atotal of 412 patients were randomized in a 1:1 ratio to receive thestudy abuse-resistant oral dosage form BID or placebo. Randomization wasstratified by both baseline PI (<7.5 vs. ≧7.5) and by the average PIover the last 2 days of the open-label titration period (<5 vs. ≧5). Thepatients were thus divided into two groups as follows: Group A, 200patients received the study abuse-resistant oral dosage form BID in adouble-blind treatment period of 12 weeks; and Group B, 200 patientsreceived placebo BID in a double-blind treatment period of 12 weeks.During the first four weeks of the double-blind treatment period,patients were titrated (up or down) to analgesic effect. At theconclusion of four weeks, the dose was fixed for an additional 8 weeks.

The primary endpoint for the clinical trial of this Example 7f was adecrease in pain intensity (AUC) between the study abuse-resistant oraldosage forms (Test Capsules) dosed BID and Placebo dosed BID during thetwelve week treatment period. Subjects that received Test Capsules BIDdemonstrated a statistically significant decrease in their painintensity-AUC as compared to the subjects that received Placebo BID andthus the study met its primary endpoint that was prospectively defined(p=0.007). The primary endpoint results (Pain Intensity—AUC for the 12week double-blind period for the analysis population:intent to treatpopulation are reported below in Table 81.

TABLE 81 TEST PLACEBO CAPSULES BID BID TOTAL (N = 207) (N = 203) (N =410) AREA UNDER CURVE (AUC) MEAN (SD) −30.4 (140.38) −54.9 (122.44)−42.5 (132.21) MEDIAN −1.5 −27.1 −9.8 MINIMUM, −501.8, 370.7 −683.3,382.8 −683.3, 382.8 MAXIMUM N 205 201 406 MODEL P-VALUES TREATMENT [1]0.007 PRE- <0.001 RANDOMIZATION PI [1]

With regard to the above-noted results in Table 81, the Intent to TreatPopulation were all randomized patients who took any study medicamentand have at least one post-randomization Pain Intensity measurement. Inaddition, the Area Under the Curve (AUC) was calculated by the LinearTrapezodial Method using change from pre-randomization pain intensityscores. The p-values reported above were from ANCOVA Model includingtreatment as the main effect and pre-randomization pain intensity as acovariate.

Secondary endpoints for the clinical trial included: pain intensity(change in pain intensity by week), quality of analgesia, globalassessment, Short Form 12 Question Health Survey (SF-12) and WesternOntario and MacMaster Universities Osteoarthritis Index (WOMAC). For thepain intensity results, the group that received the Test Capsules BIDhad consistently lower pain intensity scores at each week during thetwelve-week clinical trial as compared to the group that received thePlacebo BID (p=0.024 at week twelve). For quality of analgesia, thegroup that received Test Capsules BID showed a consistent and greaterimprovement in the quality of analgesia at each week during thetwelve-week clinical trial as compared to the group that received thePlacebo BID (p=0.004 at week twelve). For global assessment, the groupthat received Test Capsules BID showed a consistently better globalassessment at each week during the twelve week clinical trial ascompared to the group that received the Placebo BID (p=0.007 at weektwelve). For SF-12, the group that received Test Capsules BID had ahigher value for the physical component score of the SF-12 (p=0.003 atweek twelve) and for the mental component score of the SF-12 (p=0.055 atweek twelve) as compared to the group administered Placebo BID, whereinhigher values correspond to better health or functioning. For thestiffness and physical function subscales of the WOMAC, although thevalues were lower in the group administered Test Capsules BID ascompared to the group administered Placebo BID, as expected, thedifferences were not significant (stiffness subscale p=0.366 at weektwelve and physical function subscale p=0.221 at week twelve). For thepain sub scale of the WOMAC, the values (% change from baseline to weektwelve) were significantly lower in the group administered Test CapsulesBID as compared to the group administered Placebo BID (p=0.023 at weektwelve), wherein lower values correspond to better health orfunctioning. No drug-related safety issues were noted in this study.

Example 7g

This human clinical trial study was a single-center, randomized,open-label, phase I study to assess the safety and pharmacokinetics ofthree different high-dose (80 mg strength) abuse-resistant oxycodoneformulations, and to assess the performance of these against two lowerstrength (40 mg) abuse-resistant oxycodone dosage forms that used in thestudies of Examples 7a-7f above (collectively, the OXY Test Capsules).

The abuse-resistant oxycodone oral dosage forms used in this Example 7gwere prepared using the following raw materials: Oxycodone base,micronized (“OXY”); Isopropyl Myristate, NF (“IPM”); Colloidal silicondioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF(“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate(Eastman Chemicals), (“SAM”); Triacetin USP (“TA”); Sodium LaurylSulfate (“SLS”); Labrafil M2125 CS (“LAB”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize #00hard gelatin cap shells to produce 80 mg dosage forms that wereused as Test Capsules. The details of the formulations are disclosedbelow in Table 82.

TABLE 82 OXY SAIB TA CAB IPM HEC SiO₂ BHT SLS LAB (Total) OXY1 80.0281.4 208.4 42.0 112.0 42.0 14.0 0.2 — — 780 (mg) 10.26 36.08 26.72 5.3814.36 5.38 1.79 0.02 — — (wt %) OXY2 80.0 297.5 198.4 42.0 105.0 42.014.0 0.2 1.0 — 780 (mg) 10.26 38.14 25.43 5.38 13.46 5.38 1.79 0.02 0.13— (wt %) OXY3 80.0 285.5 190.3 42.0 105.0 42.0 14.0 0.2 — 21.0 780 (mg)10.26 36.60 24.40 5.38 13.46 5.38 1.79 0.02 — 2.69 (wt %) OXY10 40.0319.6 213.1 37.0 111.0 44.4 14.8 0.16 — — 780 (mg) 5.13 40.98 27.32 4.7414.23 5.69 1.9 0.02 — — (wt %)

All four treatments received dosing after an overnight fast of at least10 hours, followed by thirty minutes after the start of a standardbreakfast (8 ounces orange juice, two fried eggs, and two slices oftoast with butter and preserve). Dosing days were separated by a washoutperiod of 3 days. All subjects were administered naltrexone blockade toprevent opioid-related adverse events. Sixteen (16) healthy malesubjects enrolled in the study, and 15 completed the four treatmentperiods of the study. Plasma samples were analyzed for oxycodone using avalidated LC-MS-MS procedure.

The results of a pharmacokinetic analysis of the study results from thisExample 7g are presented below in Table 83. In addition, the oralbioavailability of oxycodone for the three 80 mg OXY Test Capsulesrelative to the 2×40 mg Test Capsules is presented in Table 84 below.

TABLE 83 OXY10 Test OXY1 Test OXY2 Test OXY3 Test Capsules ParameterCapsules Capsules Capsules (2 × 40 mg) T_(max) (hr) 4.66 ± 1.67 4.68 ±1.16 4.35 ± 1.80 4.38 ± 1.04 C_(max) (ng/mL) 61.7 ± 17.3 47.5 ± 13.552.7 ± 27.9 87.4 ± 28.8 AUC_(last) (hr * ng/mL) 903.6 ± 242.6 838.3 ±220.2 834.7 ± 331.5  1001 ± 213.8 AUC_(inf) (hr * ng/mL) 905.5 ± 245.5855.3 ± 218.7 872.6 ± 343.1  1028 ± 216.3

TABLE 84 C_(max) AUC_(last) AUC_(inf) Treatment Ratio (%) Ratio (%)Ratio (%) OXB1 vs. 70.59 90.27 88.08 OXB10 (2 × 40 mg) OXB2 vs. 54.3583.75 83.20 OXB10 (2 × 40 mg) OXB3 vs. 60.30 83.39 84.88 OXB10 (2 × 40mg)

As can be seen by these results, the pharmacokinetic profiles for thethree different high-strength Test Capsule formulations (OXY1-OXY3) werecomparable with peak oxycodone concentrations observed at 4.35 to 4.68hours. The mean C_(max) values for the three high-strength Test Capsuleformulations were 29% to 46% lower than the mean C_(max) afteradministration of the 2×40 mg Test Capsule (OXY10). Likewise, overallsystemic exposure to oxycodone after administration of the three 80 mgTest Capsule formulations (OXY1-OXY3) was lower (10% to 17%) than afteradministration of the 2×40 mg Test Capsule (OXY10). Finally, therelative bioavailability based upon the AUC_(last) of the three 80 mgTest Capsule formulations (OXY1-OXY3) was very good (>80%, ranging from83.39% to 90.27%.

Example 7h

This human clinical trial study was a single-center, randomized,open-label, phase I study to assess the safety and pharmacokinetics ofthree different high-dose (80 mg strength) abuse-resistant oxycodoneformulations, and to assess the performance of these against two lowerstrength (40 mg) abuse-resistant oxycodone dosage forms that used in thestudies of Examples 7a-7f above (collectively, the OXY Test Capsules).

The abuse-resistant oxycodone oral dosage forms used in this Example 7hwere prepared using the following raw materials: Oxycodone base,micronized (“OXY”); Isopropyl Myristate, NF (“IPM”); Colloidal silicondioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF(“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate(Eastman Chemicals), (“SAM”); Triacetin USP (“TA”); Sodium LaurylSulfate (“SLS”); Labrafil M2125 CS (“LAB”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize #00hard gelatin cap shells to produce 80 mg dosage forms that wereused as Test Capsules. The details of the formulations are disclosedbelow in Table 85.

TABLE 85 OXY SAIB TA CAB IPM HEC SiO₂ BHT SLS LAB (Total) OXY4 80.0280.4 207.7 36.7 119.0 42.0 14.0 0.2 — — 780 (mg) 10.26 35.95 26.63 4.7115.26 5.38 1.79 0.02 — — (wt %) OXY5 80.0 281.0 200.8 42.0 119.0 42.014.0 0.2 1.0 — 780 (mg) 10.26 36.03 25.74 5.38 15.26 5.38 1.79 0.02 0.13— (wt %) OXY6 80.0 286.6 191.0 36.7 112.0 42.0 14.0 0.2 — 17.5 780 (mg)10.26 36.74 24.49 4.71 14.36 5.38 1.79 0.02 — 2.24 (wt %) OXY10 40.0319.6 213.1 37.0 111.0 44.4 14.8 0.16 — — 780 (mg) 5.13 40.98 27.32 4.7414.23 5.69 1.9 0.02 — — (wt %)

All four treatments received dosing after an overnight fast of at least10 hours, followed by thirty minutes after the start of a standardbreakfast (8 ounces orange juice, two fried eggs, and two slices oftoast with butter and preserve). Dosing days were separated by a washoutperiod of 3 days. All subjects were administered naltrexone blockade toprevent opioid-related adverse events. Sixteen (16) healthy malesubjects enrolled in the study, and completed the four treatment periodsof the study. Plasma samples were analyzed for oxycodone using avalidated LC-MS-MS procedure.

The results of a pharmacokinetic analysis of the study results from thisExample 7h are presented below in Table 86. In addition, the oralbioavailability of oxycodone for the three 80 mg OXY Test Capsulesrelative to the 2×40 mg Test Capsules is presented in Table 87 below.

TABLE 86 OXY10 Test OXY4 Test OXY5 Test OXY6 Test Capsules ParameterCapsules Capsules Capsules (2 × 40 mg) T_(max) (hr) 4.44 ± 1.72 4.47 ±2.38 4.55 ± 1.52 4.22 ± 1.16 C_(max) (ng/mL) 75.5 ± 28.7 65.7 ± 27.769.9 ± 20.8 91.0 ± 30.5 AUC_(last) (hr * ng/mL)  1020 ± 340.9 954.0 ±315.0  1023 ± 296.4 966.2 ± 267.6 AUC_(inf) (hr * ng/mL)  1069 ± 415.7964.8 ± 319.6  1037 ± 301.6 981.4 ± 264.0

TABLE 87 C_(max) AUC_(last) AUC_(inf) Treatment Ratio (%) Ratio (%)Ratio (%) OXB4 vs. 82.97 105.57 108.93 OXB10 (2 × 40 mg) OXB5 vs. 72.2098.74 98.31 OXB10 (2 × 40 mg) OXB6 vs. 76.81 105.88 105.67 OXB10 (2 × 40mg)

As can be seen by these results, the pharmacokinetic profiles for thethree different high-strength Test Capsule formulations (OXY4-OXY6) werecomparable with peak oxycodone concentrations observed at 4.44 to 4.55hours. The mean C_(max) values for the three high-strength Test Capsuleformulations were 17% to 28% lower than the mean C_(max) afteradministration of the 2×40 mg Test Capsule (OXY10). However, overallsystemic exposure to oxycodone after administration of the three 80 mgTest Capsule formulations (OXY4-OXY6) was comparable to that afteradministration of the 2×40 mg Test Capsule (OXY10). Finally, therelative bioavailability based upon the AUC_(last) of the three 80 mgTest Capsule formulations (OXY4-OXY6) was nearly complete, ranging from98.74% to 105.88%.

Example 8 In Vivo Abuse Resistance Evaluation of Formulations

Human drug-liking studies have demonstrated that reward increases withthe rate of rise in drug blood levels; wherein the faster influx of druginto the blood provides a better rush or high. Savage et al. (2008)Addict Sci Clin Pract 4(2):4-25; Marsch et al. (2001) J Pharmacol ExpTher 2001 299(3):1056-1065. A study to determine which properties ofprescription opioids make them more attractive for the purposes of abusesupported the speed of onset as a key factor. Butler et al. (2006) HarmReduct J 2006 3:5.

Prescription drug abusers manipulate sustained-release (“SR”) opioidformulations to dose dump (rapidly release) the active agent andincrease the rate of rise to achieve the desired high. Common methods ofSR opioid abuse are chewing, crushing and extracting and then orallyingesting, snorting or injecting the opioid active agent to achieve ahigh. In experienced casual abusers may chew or crush SR opioids and mixthe manipulated drug with alcohol. As casual abusers generally have nodrug tolerance, dose dumping of the opioid active agent poses asignificant health risk and may even lead to accidental and potentiallyfatal overdose.

In order to investigate the extent of dose dumping that occurs afterphysical manipulation of the currently available SR formulation ofoxycodone (OxyContin, hereinafter the “SR Control”)), the followingphase I study was conducted in five healthy male volunteers. The lowestSR Control dose (10 mg) was chosen to optimize safety for thevolunteers. The SR Control tablets were crushed using a mortar andpestle, and the manipulated dosage forms were administered to volunteerswith water or 40 proof alcohol and compared against SR Control tabletsswallowed whole and to a 10 mg dose of an immediate release formulationof oxycodone (Roxycodone, 2×5 mg).

The results of the study are provided below in Table 88, and depicted inFIG. 24.

TABLE 88 SR Control 10 mg Oxycodone IR 2 × 5 mg Whole Whole ParameterMean (Std Dev) Mean (Std Dev) T_(max) (hr) 1.91 (0.90) 1.35 (0.95)C_(max) (ng/mL) 6.82 (1.26) 18.9 (4.86) SR Control 10 mg SR Control 10mg Crushed/Water Crushed/Alcohol Parameter Mean (Std Dev) Mean (Std Dev)T_(max) (hr) 0.90 (0.22) 0.95 (0.41) C_(max) (ng/mL) 21.8 (5.84) 21.0(8.24)

As can be seen by these results, crushing the SR Control tablets andingesting with water or alcohol significantly increased both the rateand extent of absorption of oxycodone (see FIG. 24). In particular, theC_(max) increased from 6.82 ng/mL to 21.8 and 21.0 ng/mL for the SRControl with water or alcohol, respectively. This C_(max) was verysimilar to that obtained with the oxycodone IR tablets (18.9 ng/mL).Similarly, T_(max) decreased from 1.91 hours to 0.90 and 0.95 aftercrushing with water or alcohol, respectively. These T_(max) values wereshorter than the T_(max) obtained with the IR tablets (1.35 hour).

The total AUC is a pharmacological metric that represents the totalamount of active agent absorbed. The AUC to a specific time, i.e., thecumulative AUC, represents the amount of active agent absorbed to thattime, and allows one to assess the rate of increase in exposure. Thisautomatically corrects for differences in bioavailability and allows atrue comparison among treatments and/or formulations. The rapid rate ofabsorption and the loss of controlled-release mechanism after physicalmanipulation of the SR Control tablets are evident from FIG. 24 whichshows that the rate of absorption is significantly increased.

An Abuse Quotient, or AQ, can be used as a method to express theattractiveness for abuse of a formulation/dosage form. Webster LR (2007)Emerging opioid formulations: abuse deterrent or abuse resistant?[Internet] Available from:http:www.emergingsolutionsinpain.com/opencms/esp/commentaries/index.html.The AQ takes into account the observation that increasing C_(max) anddecreasing T_(max) increases the attractiveness of a particular dosageform for abuse. Represented as a formula, AQ=C_(max)/T_(max). In theinstant study, the AQ was 3.57 for the SR Control taken intact and 14.0for the immediate release tablets. After crushing the SR Control withwater or ethanol, the AQ for the SR Control increased to 24.2 and 22.2,respectively, suggesting that the attractiveness of the SR Control forabuse was greatly increased after physical manipulation. AQ is a dosedependent metric as C_(max) varies with dose. For ease of comparison ofthis initial study with subsequent in vivo abuse resistance evaluationsof the abuse-resistant dosage forms of the present invention with doselevels of 40 mg, the equivalent AQ after dose adjustment would be 14.3of the SR Control (40 mg) taken intact and 56.0 for the immediaterelease (40 mg). After crushing the SR Control with water or alcohol,the dose adjusted AQ would increase to 96.8 and 88.8, respectively.

Accordingly, four Phase I In Vivo Abuse Resistance Evaluation studieswere conducted to challenge abuse-resistant dosage forms of the presentinvention using physical and chemical manipulation in order to attemptto include dose dumping or immediate-release effect. Since food effectstudies with the relevant dosage forms indicated that administrationwith food significantly increase the rate and the extent of absorptionof oxycodone from the abuse-resistant dosage forms, all PK studiesdescribed in this Example 8 administered the Test Capsules with food,while reference oxycodone IR oral solution was administered underfasting conditions as a benchmark for the most rapid absorption ofoxycodone. Subjects in all PK studies were pretreated with naltrexone tominimize opioid-related side effects.

In all of the In Vivo Abuse Resistance Evaluation studies describedbelow, plasma samples were analyzed for oxycodone, noroxycodone, andoxymorphone by CEDRA Corporation using a validated LC-MS-MS procedure.The method was validated for a range of 0.250 to 125 ng/mL foroxycodone, 0.500 to 250 ng/mL for noroxycodone and 0.0500 to 25.0 ng/mLfor oxymorphone. Data were analyzed by noncompartmental methods inWinNonlin. Concentration-time data that were below the limit ofquantification (BLQ) were treated as zero (0.00 ng/mL) in the datasummarization and descriptive statistics. In the pharmacokineticanalyses, BLQ concentrations were treated as zero from time-zero up tothe time at which the first quantifiable concentration was observed;embedded and/or terminal BLQ concentrations were treated as “missing”.

The abuse-resistant oxycodone oral dosage forms used in the studies wereprepared using the following raw materials: Oxycodone base, micronized(“OXY”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize 00 white opaque gel cap shells to produce 5, 10, 20, 30 and 40 mgdosage forms that were used as the OXY Test Capsules. The details of theformulations and the dosage forms containing the formulations of thisExample 8 are disclosed below in Tables 89 and 90.

TABLE 89 OXY SAIB TA CAB IPM HEC SiO₂ BHT (wt %) (wt %) (wt %) (wt %)(wt %) (wt %) (wt %) (wt %) 5.13 40.98 27.32 4.74 14.23 5.69 1.9 0.02

TABLE 90 Capsule OXY SAIB TA CAB IPM HEC SiO₂ BHT Total Strength (mg)(mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg)  5 mg 5.0 40.0 26.6 4.6 13.9 5.51.8 0.02 97.5 10 mg 10.0 79.9 53.3 9.2 27.7 11.1 3.7 0.04 195.0 20 mg20.0 159.8 106.5 18.5 55.5 22.2 7.4 0.08 390.0 30 mg 30.0 239.7 159.827.8 83.2 33.3 11.1 0.12 585.0 40 mg 40.0 319.6 213.1 37.0 111.0 44.414.8 0.16 780.0

Example 8a

The following In Vivo Abuse Resistance Evaluation study was asingle-center, four-way crossover PK study to assess the effect ofphysical disruption of the controlled release carrier system on therelease of the oxycodone active agent from abuse-resistant oral dosageforms produced according to the present invention. The study dosageforms (capsules containing oxycodone free base, 40 mg) (“OXY” TestCapsules) were administered (fed state) intact or crushed with alcohol.For comparison, oxycodone sustained release (SR) tablets (OxyContinbrand sustained release Oxycodone tablets, 40 mg, Purdue Pharma), “SRControl” were administered (fasting state) intact or crushed withalcohol, as well as 40 mg oral solution of oxycodone HCl as a comparatorof an immediate release (“IR Control”) (fasting state) in order torepresent a “worst-case scenario”. Subjects were administered naltrexoneblockade to prevent opioid-related adverse events. Fifty subjects wereenrolled in this study, 27 males and 23 females. One male did notcomplete the study and another male experienced emesis within 12 hoursof dosing; 48 subjects were included in the PK analysis.

The mean linear and semi-logarithmic oxycodone plasma concentration-timecurves obtained in this Example 8a study are depicted in FIG. 26. TheC_(max) and T_(max) values, based on mean oxycodone plasmaconcentration-time values, are presented below in Table 91, and meanoxycodone PK parameters from noncompartmental analysis of individualdata obtained in the Example 8a study are presented below in Table 92.

TABLE 91 SR SR IR OXY OXY Control Control Control 40 mg 40 mg 40 mg 40mg 40 mg Param- Capsule- Capsule- Tablet- Tablet- Oral eter WholeCrushed Whole Crushed Solution T_(max) 4.50 3.00 2.00 1.50 1.00 (hr)C_(max) 36.8 71.3 38.4 76.7 86.0 ng/mL)

TABLE 92 Treatment A: Treatment B: OXY (40 mg Capsule-Whole) OXY (40 mgCapsule-Crushed) Parameter n Mean SD CV % n Mean SD CV % T_(max) (hr) 395.15 2.24 43.46 40 2.97 0.97 32.51 C_(max) (ng/mL) 39 43.8 18.4 41.98 4078.8 10.5 13.30 AUC₀₋₂ (hr*ng/mL) 39 13.15 9.533 72.51 40 54.88 25.1345.78 AUC₀₋₄ (hr*ng/mL) 39 64.62 35.87 55.51 40 192.0 34.06 17.74 AUC₀₋₆(hr*ng/mL) 39 132.2 52.80 39.93 40 303.6 41.73 13.74 AUC₀₋₁₂ (hr*ng/mL)39 289.5 76.69 26.49 40 461.6 69.02 14.95 AUG₀₋₂₄ (hr*ng/mL) 39 443.7108.0 24.35 40 557.4 96.09 17.24 AUC₀₋₄₈ (hr*ng/mL) 30 555.6 133.8 24.0812 665.3 103.7 15.59 AUC_(last) (hr*ng/mL) 39 534.6 143.6 26.85 40 569.7109.7 19.26 AUC_(inf) (hr*ng/mL) 27 585.8 143.5 24.49 9 677.6 96.0714.18 AUC_(Extrap) (%) 27 1.79 1.73 96.25 9 0.48 0.16 34.12 λ_(z) (hr⁻¹)27 0.0804 0.0215 26.77 9 0.1081 0.0082 7.55 T_(1/2) (hr) 27 9.30 2.8030.13 9 6.45 0.53 8.18 T_(last) (hr) 39 50.46 18.91 37.47 40 31.80 12.6139.67 C_(last) (ng/mL) 39 1.57 2.19 140.07 40 1.41 0.943 67.01 TreatmentC: Treatment D: SR Control (40 mg Tablet-Whole) SR Control (40 mgTablet-Crushed) Parameter n Mean SD CV % n Mean SD CV % T_(max) (hr) 402.09 0.97 46.55 39 1.48 0.66 44.38 C_(max) (ng/mL) 40 42.3 9.82 23.20 3988.4 27.4 30.97 AUC₀₋₂ (hr*ng/mL) 40 50.30 12.55 24.95 39 109.1 39.6136.31 AUC₀₋₄ (hr*ng/mL) 40 123.0 26.47 21.52 39 215.8 63.13 29.26 AUC₀₋₆(hr*ng/mL) 40 185.2 39.97 21.58 39 281.4 75.94 26.98 AUC₀₋₁₂ (hr*ng/mL)40 300.3 67.32 22.42 39 372.5 102.6 27.55 AUG₀₋₂₄ (hr*ng/mL) 39 398.596.38 24.19 39 423.7 123.5 29.14 AUC₀₋₄₈ (hr*ng/mL) 16 507.8 122.2 24.062 619.3 197.6 31.90 AUC_(last) (hr*ng/mL) 40 422.5 117.8 27.89 39 425.2126.1 29.65 AUC_(inf) (hr*ng/mL) 16 512.4 122.0 23.81 2 621.9 197.431.75 AUC_(Extrap) (%) 16 0.85 0.50 58.88 2 0.43 0.17 38.58 λ_(z) (hr⁻¹)16 0.0995 0.0144 14.43 2 0.1022 0.0103 10.08 T_(1/2) (hr) 16 7.12 1.1315.86 2 6.81 0.69 10.08 T_(last) (hr) 40 33.90 13.55 39.98 39 25.24 5.3621.24 C_(last) (ng/mL) 40 2.23 2.33 104.51 39 0.951 0.587 61.78Treatment E: IR Control (40 mg Oral Solution) Parameter n Mean SD CV %T_(max) (hr) 40 0.97 0.25 25.60 C_(max) (ng/mL) 40 91.6 26.3 28.67AUC₀₋₂ (hr*ng/mL) 40 128.3 34.84 27.15 AUC₀₋₄ (hr*ng/mL) 40 230.5 55.9324.26 AUC₀₋₆ (hr*ng/mL) 40 291.9 70.74 24.24 AUC₀₋₁₂ (hr*ng/mL) 40 374.795.82 25.57 AUG₀₋₂₄ (hr*ng/mL) 40 419.6 112.8 26.89 AUC₀₋₄₈ (hr*ng/mL)40 425.7 116.2 27.30 AUC_(last) (hr*ng/mL) 40 421.3 114.9 27.28AUC_(inf) (hr*ng/mL) 40 426.4 116.9 27.42 AUC_(Extrap) (%) 40 1.16 0.5849.56 λ_(z) (hr⁻¹) 40 0.1765 0.0311 17.62 T_(1/2) (hr) 40 4.08 1.0325.36 T_(last) (hr) 40 25.50 8.67 34.00 C_(last) (ng/mL) 40 0.883 0.56363.78

As can be seen from these results, the following comparisons andconclusions can be drawn.

1. Treatment A vs. B: (OXY Test Capsule 40 mg capsule (whole) vs. OXYTest Capsule 40 mg capsule (crushed), extracted with 40% ethanol). The90% confidence interval for comparing the maximum exposure, based onln(C_(max)), was outside the required 80% to 125% limits for oxycodone.The C_(max) values of the crushed Test Capsules were nearly twice asthat of the intact Test Capsules and the time to reach the maximumconcentration (T_(max)) was earlier with the crushed Test Capsules (2.97hours vs. 5.15 hours). The 90% confidence intervals for comparing totalsystemic exposure, based on ln(AUC_(last)) and ln(AUC_(inf)), werewithin the accepted 80% to 125% limits for oxycodone. The 90% confidenceintervals for comparing the earlier systemic exposure, ln(AUC₀₋₂),ln(AUC₀₋₄), ln(AUC₀₋₆), and ln(AUC₀₋₁₂), and a later exposureln(AUC₀₋₂₄) were outside the 80% to 125% limits for oxycodone. However,ln(AUC₀₋₄₈) was within the 80% to 125% limits.

2. Treatment D vs. E: (SR Control (OxyContin) 40 mg tablet (crushed,extracted with 40% ethanol) vs. IR Control (Oxycodone HCl) oral solution40 mg). The 90% confidence interval for comparing the maximum exposureof the SR Control, based on ln(C_(max)), was within the required 80% to125% limits for the IR Control (oxycodone). The 90% confidence intervalfor comparing total systemic exposure, based on ln(AUC_(last)), waswithin the accepted 80% to 125% limits for the IR Control. The 90%confidence intervals for comparing the earlier systemic exposure,ln(AUC₀₋₄), ln(AUC₀₋₆), and ln(AUC₀₋₁₂), and the later systemic exposureln(AUC₀₋₂₄) were also within the 80% to 125% limits for the IR Control.

3. Treatment B vs. E: (OXY Test Capsules 40 mg capsule (crushed,extracted with 40% ethanol) vs. IR Control (Oxycodone HCl) oral solution40 mg). The 90% confidence interval for comparing the maximum exposureof the crushed Test Capsules, based on ln(C_(max)), was within therequired 80% to 125% limits for the IR Control. The time to reach themaximum concentration (T_(max)) took longer with the crushed TestCapsules than with the IR Control (2.97 hours vs. 0.97 hours). The 90%confidence intervals for comparing total systemic exposure, based onln(AUC_(last)) and ln(AUC_(inf)), were outside the accepted 80% to 125%limits for the IR Control. The 90% confidence intervals for comparingthe earlier systemic exposure, ln(AUC₀₋₂), ln(AUC₀₋₄), and ln(AUC₀₋₁₂),and the later systemic exposures ln(AUC₀₋₂₄) and ln(AUC₀₋₄₈) were alsooutside the 80% to 125% limits for the IR Control.

4. Treatment B vs. D: (OXY Test Capsules 40 mg capsule (crushed,extracted with 40% ethanol) vs. SR Control 40 mg tablet (crushed,extracted with 40% ethanol). The 90% confidence interval for comparingthe maximum exposure of both the OXY Test Capsules and the SR Control,based on ln(C_(max)), was within the required 80% to 125% limits for theIR Control. However, the time to reach the maximum concentration(T_(max)) took twice as long with the crushed Test Capsules than withthe SR Control (2.97 hours vs. 1.48 hours). The 90% confidence intervalsfor comparing total systemic exposure, based on ln(AUC_(last)) wereoutside the accepted 80% to 125% limits for the IR Control. The 90%confidence intervals for both test compositions comparing the earliersystemic exposure, ln(AUC₀₋₂), ln(AUC₀₋₄), and ln(AUC₀₋₆) were withinthe required 80% to 125% limits. However the intermediate values ofsystemic exposure, ln(AUC₀₋₁₂) and the later systemic exposureln(AUC₀₋₂₄) were outside the required 80% to 125% limits for bothcompositions.

5. Treatment C vs. D: (SR Control 40 mg tablet (whole) vs. SR Control 40mg tablet (crushed, extracted with 40% ethanol)). The 90% confidenceinterval for comparing the maximum exposure, based on ln(C_(max)), wasoutside the required 80% to 125% limits for the IR Control. The time toreach the maximum concentration (T_(max)) was slightly longer with theintact SR Control tablet versus the SR Control crushed tablet (2.09hours vs. 1.48 hours). The 90% confidence intervals for comparing thelater systemic exposure, ln(AUC₀₋₂₄) and the total systemic exposure,based on ln(AUC_(last)), were within the accepted 80% to 125% limits.The 90% confidence intervals for comparing the earlier systemicexposure, ln(AUC₀₋₂), ln(AUC₀₋₄), and ln(AUC₀₋₆) and intermediate valuesof systemic exposure, ln(AUC₀₋₁₂) were outside the 80% to 125% limits.

Furthermore, the cumulative AUC of oxycodone (0-6 hours) after oraladministration of single doses of 40 mg OXY Test Capsules (whole orcrushed and extracted with 40% ethanol) and 40 mg SR Control tabletsswallowed whole or crushed and extracted with 40% ethanol, and a single40 mg oxycodone solution IR Control are depicted in FIG. 27. As can beseen by reference to this figure, and the above tabulated PK results,the C_(max) of the OXY Test Capsules increased from 43.8±18.4 ng/mL to78.8±10.5 ng/mL and the T_(max) decreased from 5.15±2.24 h to 2.97±0.97h. However, crushing and extracting the OXY Test Capsules with 40%ethanol did not affect the extent of total absorption, and regardless ofthe means used to manipulate the instant abuse-resistant dosage forms,absorption was 3-fold slower that after administration of the IR Control(mean T_(max) was 0.97±0.25 h). The rate of absorption and peak exposureto oxycodone after the OXY Test Capsules were crushed and extracted with40% ethanol were also lower than those for the SR Control tablets(T_(max) was 1.48 while C_(max) was 88.4 ng/mL). It was noted that at 1hour post administration, oxycodone plasma concentrations after the OXYTest Capsules were crushed and extracted with 40% ethanol were lowerthan those after the SR Control was taken intact. The cumulative percentof the total area under the oxycodone plasma concentration vs. timeresults are depicted in FIG. 28 for each of the study dosage forms. Ascan be seen, FIG. 28 shows that based upon the cumulative percent oftotal AUC, the rate of exposure for OXY Test Capsules after crushing andextraction (40% ethanol) remains substantially lower than that for boththe SR Control tablets after crushing and extraction and the IR Controlsolution, with a particularly pronounced difference during the initialhours after administration.

Finally, the AQ calculations for this Example 8A study were as follows:OXY Test Capsules (intact), AQ=8.5 and OXY Test Capsules (crushed andextracted), AQ=26.5; SR Control (intact), AQ=20.2, SR Control (crushedand extracted), AQ=59.7; and IR Control, AQ=94.3.

Example 8b

The following In Vivo Abuse Resistance Evaluation studies weresingle-center, three-way crossover PK studies to determine the releaserate of oxycodone after dissolving the study abuse-resistant oral dosageforms (capsules containing oxycodone free base, 40 mg, “OXY” TestCapsules) in the buccal cavity of healthy volunteers. The 40 mg studydosage forms were administered (fed state) and allowed to dissolve inthe buccal cavity for 10 minutes to compare with 40 mg study dosageforms administered (fed state) intact, and a 40 mg oral solution ofimmediate release (IR) oxycodone HCl (“IR Control”) (fasting state) inorder to represent a “worst-case scenario”. Subjects were administerednaltrexone blockade to prevent opioid-related adverse events. A total of48 healthy adult male and female volunteers were enrolled. Forty-two(42) of the 48 subjects enrolled in the first study completed the study(3 subjects experienced emesis within 12 hours of dosing and 3 subjectsdid not complete required treatments; and all 6 were thus excluded fromthe PK analysis). Fourty-four (44) of the 48 subjects enrolled in thesecond study completed the study; however, 2 subjects who completed thestudy experienced emesis with 12 hours of dosing and were thereforeexcluded from the PK analysis).

Mean oxycodone plasma concentrations (0-6 hours) obtained from the firstExample 8b in vivo abuse resistance study are depicted in FIG. 29, TheC_(max) and T_(max) values from the first and second Example 8b studies,based on mean oxycodone plasma concentration-time values, are presentedbelow in Tables 93 and 94, respectively.

TABLE 93 OXY Test OXY Test Capsule Capsule Dissolved in IR ParameterWhole Buccal Cavity Control T_(max) (hr) 4.50 3.00 1.00 C_(max) (ng/mL)36.2 64.6 76.6

TABLE 94 OXY Test OXY Test Capsule Dissolved Capsule Whole in BuccalCavity IR Control Parameter Mean (Std Dev) Mean (Std Dev) Mean (Std Dev)T_(max) 5.61 (2.32) 2.89 (0.79) 1.15 (0.62) (hr) C_(max) 41.80 (16.30)71.10 (14.20) 86.70 (30.80) (ng/mL) AUC₀₋₂ 12.12 (8.49)  48.44 (22.49)116.80 (31.32)  (hr*ng/mL) AUC_(last) 547.60 (226.90) 596.20 (177.20)434.10 (148.40) (hr*ng/mL)

As can be seen by these results, holding the OXY Test Capsules in thebuccal cavity for 10 minutes did not result in rapid transmucosalabsorption of oxycodone as indicated by the lack of difference in meanplasma concentrations during the very early sampling time points betweenbuccal and whole treatments. In addition, the total extent of exposureto oxycodone was not affected by holding the OXY Test Capsules in thebuccal cavity.

The AQ for the OXY Test Capsules administered intact in this study was7.5, while the AQ for OXY Test Capsules after holding in the buccalcavity was 24.6. However, the AQ for the IR Control was much greater(75.4), suggesting that the attractiveness of the instantabuse-resistant dosage forms was much less than abuse of an oralsolution of oxycodone.

Example 8c

The following In Vivo Abuse Resistance Evaluation study was asingle-center, randomized crossover study to assess the effect ofrigorous mastication on the rate and extent of absorption of 40 mgoxycodone base in abuse-resistant oral dosage forms in comparison withthe same dosage forms swallowed whole (both under fed conditions) and anoxycodone immediate release solution under fasted conditions. A total of48 healthy subjects (29 males, 19 females) were enrolled in the study.Subjects were administered naltrexone blockade to block opioid-relatedeffects. Four subjects (2 each male and female) did not complete thestudy, and a total of 44 subjects were thus included in the PK analysis.

The PK results from this Example 8c study are reported below in Table95. In addition, the cumulative percent (mean) of the total area underthe oxycodone plasma concentration vs. time curve data are depicted inFIG. 30.

TABLE 95 OXY Test OXY Test Capsule Whole Capsule Chewed IR ControlParameter Mean (Std Dev) Mean (Std Dev) Mean (Std Dev) T_(max) 5.52(1.83) 2.67 (0.78)  1.07 (0.46) (hr) C_(max) 40.50 (18.80) 82.30 (16.70)102.00 (33.40) (ng/mL) AUC₀₋₂ 8.32 (5.75) 64.09 (27.94) 138.80 (40.12)(hr*ng/mL) AUC_(last) 512.50 (118.30) 596.80 (134.40) 455.80 (113.60)(hr*ng/mL)

As can be seen, vigorous mastication (chewing) of the OXY Test Capsulesincreased the mean C_(max) from 40.5 ng/mL to 82.3 ng/mL. However,relative to the IR Control oral solution, the C_(max) for the chewedTest Capsules was significantly lower and occurred at a significantlylater time. The mean T_(max) for the chewed OXY Test Capsules decreasedfrom 5.52 hours to 2.67 hours, as compared to 1.07 for the IR Controloral solution. The total extent of absorption was not affected bychewing the OXY Test Capsules. These data indicate that chewing (acommon form of abuse) of the abuse-resistant dosage forms of the presentinvention did not defeat the controlled release mechanism of theformulations, as evident from the lack of dose dumping and plasmaconcentration profiles that retained a broad plateau.

Finally, the AQ for the Test Capsules (intact) was 7.3, whereas the AQfor the chewed Test Capsules was 30.8. However, the AQ for thecomparator oral solution was 95.3.

Example 8d

The following In Vivo Abuse Resistance Evaluation study was asingle-center, four-way crossover PK study to determine the rate andextent of absorption of 40 mg oxycodone base in abuse-resistant oraldosage forms when co-administered with 240 mL of 4% ethanol, 20% ethanoland 40% ethanol in comparison to 240 mL of water (fed state). A total of37 healthy adult male and female volunteers received at least one doseof the study dosage forms. Subjects were administered naltrexoneblockade to block opioid-related effects. Because of the largequantities of alcohol administered, a large percentage of subjectsexperienced emesis. Approximately 25% of subjects vomited afterreceiving 20% ethanol and 38% of subjects vomited after receiving 40%ethanol. Pharmacokinetic blood sampling for a given treatment period wasdiscontinued after emesis. After the second treatment period of thestudy, it was decided not to allow any additional female subjects toreceive the study dosage forms with 40% ethanol, since all femalesubjects receiving this treatment had vomited. Therefore, data for the40% ethanol treatment is only available for 18 subjects.

In this study, the total volume of liquid given with administration ofthe study dosage form was 480 mL, compared to 240 mL in previous (PhaseI) studies. It appears that in the absence of alcohol, the relativelylarge volume of water resulted in the physiological response of rapidstomach emptying as evidenced by the shorter T_(max) relative to thatseen in the previous studies.

The mean linear and semi-logarithmic oxycodone plasma concentration-timecurves from the study in this Example 8d are shown in FIG. 31. TheC_(max) and T_(max) values, based on mean oxycodone plasmaconcentration-time values, are presented below in Table 96, meanoxycodone PK parameters from noncompartmental analysis of individualdata from the study in this Example 8d are presented below in Table 97.

TABLE 96 40 mg 40 mg 440 mg 40 mg OXY (w/ OXY (w/ OXY (w/ OXY (w/Parameter water) 4% EtOH) 20% EtOH) 40% EtOH) T_(max) (hr) 3.33 4.674.67 4.67 C_(max) (ng/mL) 36.8 37.7 32.8 39.9

TABLE 97 40 mg OXY 40 mg OXY 40 mg OXY 40 mg OXY (w/water) (w/4% EtOH)(w/20% EtOH) (w/40% EtOH) Parameter Mean (SD) Mean (SD) Mean (SD) Mean(SD) T_(max) (hr) 4.02 (1.29)  4.37 (1.79)  5.14 (1.55)  4.13 (1.95) C_(max) (ng/mL) 45.3 (23.1)  45.0 (20.6)  39.0 (16.1)  49.7 (27.2) AUC_(last) (hr*ng/mL) 471.3 (154.6) 471.8 (147.5) 496.3 (153.6) 537.7(191.5) AUC_(inf) (hr*ng/mL) 513.8 (156.5) 516.0 (144.1) 542.5 (144.6)585.3 (184.3)

In the statistical analysis for this Example 8d, the ratios ofco-ingestion with alcohol to co-ingestion with water were calculated formaximum exposure (C_(max)) and total exposure (AUC_(last)), and thesedata are shown below in Table 98. As can be seen, there was nosignificant effect from the co-ingestion of alcohol on the maximumexposure and extent of oxycodone absorption from abuse-resistant oraldosage forms of the present invention.

TABLE 98 Coadministration Coadministration Coadministration Parameterw/4% EtOH w/20% EtOH w/40% EtOH C_(max) Ratio* 0.99 0.86 1.10 AUC Ratio*1.00 1.05 1.14 *Ratio of average values when co-ingested with alcoholcompared to co-ingested with water

The cumulative AUC of oxcodone (0-6 h) after administration of a single40 mg OXY Test Capsule with water, 4% EtOH, 20% EtOH and 40% EtOH dataare depicted in FIG. 32. As can be seen, the mean plasma concentrationprofiles across all treatment groups were similar and displayed atypical controlled release pattern, indicating that there was no dosedumping as a result of co-ingestion with the various strengths ofalcohol. In addition, comparison of C_(max) and AUC_(last) between eachethanol treatment and water demonstrated no effect (4% EtOH), a smalldecrease in C_(max) (20% EtOH) and a 10% increase in C_(max) with onlythe highest alcohol strength tested (40% EtOH).

Example 9 In Vivo Analysis of Formulations

(Human Clinical Trails, Pharmacokinetic Studies)

In order to assess the in vivo controlled release performance ofabuse-resistant hydromorphone oral dosage forms prepared in accordancewith the present invention, the following human clinical trails werecarried out. In the studies described below, plasma samples wereanalyzed for hydromorphone using a validated LC-MS-MS procedure.

Example 9a

The abuse-resistant hydromorphone oral dosage forms used in this studywere prepared using the following raw materials: Hydromorphone HCl,(“HMH”); Isopropyl Myristate, NF (IPM); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAIB”); Triacetin USP (“TA”); and Cellulose AcetateButyrate, grade 381-20 BP, ethanol washed (Eastman Chemicals) (“CAB”).The formulations were produced using the commercial-scale manufacturingmethods (Process Schemes 4 or 5 as described above) and then filled intosize 00 white opaque gel cap shells to produce 16 mg dosage forms thatwere used as Test Capsules. The details of the HMH Test Capsuleformulations of this Example 9a are disclosed below in Table 99.

TABLE 99 HMH BHT HCl SAIB TA CAB IPM HEC SiO₂ (wt (wt %) (wt %) (wt %)(wt %) (wt %) (wt %) (wt %) %) 5.82 39.49 29.25 5.65 15.07 2.83 1.880.02

This human clinical trial study was a single-center food effect, PKstudy to determine the rate and extent of absorption of hydromorphonefrom 16 mg strength abuse-resistant oral dosage forms when administeredin a fasted state and after consumption of a meal. The comparison wasagainst an 8 mg single dose of Dilaudid brand hydromorphone HCl oralsolution administered in a fasting state. The study was conducted inhealthy, adult male and female volunteers. There were 12 subjects ineach study group (fed and fasted). Subjects were administered naltrexoneblockade to prevent opioid-related adverse events. The fed group wereadministered a “standard” meal that consisted of 8 oz orange juice, twofried eggs, and two slices of toast with butter and preserve.

The mean PK results from this Example 9a study are presented below inTable 100. The results from the pharmacokinetic analysis are reportedbelow in Table 101.

TABLE 100 HMH Test HMH Test Capsules Capsules IR Control Parameter(Fasted) (Fed) (Fasted) T_(max) (hr) 4 6 0.5 C_(max) (ng/mL) 1.52 ± 1.621.23 ± 1.13 9.17 ± 2.69 43.04 ± 22.80 52.63 ± 21.34

TABLE 101 HMH Test HMH Test Capsules Capsules IR Control Parameter(Fasted) (Fed) (Fasted) T_(max) (hr) 9.13 ± 8.31 11.6 ± 9.60 0.67 ± 0.31C_(max) (ng/mL)  1.7 ± 1.60 1.99 ± 1.29 10.5 ± 2.27 AUC_(last) 33.28 ±18.24 40.81 ± 21.52 43.67 ± 7.81  (hr*ng/mL) AUC_(inf) 39.84 ± 27.1751.24 ± 22.10 46.76 ± 6.53  (hr*ng/mL)

As can be seen by these results, food has an effect on both the rate andextent of absorption of hydromorphone from the study abuse-resistantoral dosage forms, where oral bioavailability is increased under fedconditions relative to administration of dosage forms in the fastedstate.

Example 9b

The abuse-resistant hydromorphone oral dosage forms used in this Example9b were prepared using the following raw materials: Hydromorphone HCl(“HMH”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); Labrafil M2125 CS (“LAB”);and Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (EastmanChemicals) (“CAB”). The formulations were produced using the GMPmanufacturing method of Example 1d above (Process Scheme 8) and thenfilled into size #2 gel cap shells to produce 8 and 16 mg dosage formsthat were used as the HMH Test Capsules. The details of the formulationsand the dosage forms containing the formulations of this Example 9b aredisclosed below in Table 102.

TABLE 102 Formula # HMH SAIB TA CAB IPM HEC SiO₂ BHT LAB Total HMH1 16.0104.1 77.1 15.5 41.4 15.5 5.2 0.1 — 275.0 (mg) 5.82 37.86 28.05 5.6515.07 5.65 1.88 0.02 — (wt %) HMH2 16.0 101.1 74.9 15.5 38.9 15.5 5.20.1 7.8 275.0 (mg) 5.82 36.78 27.24 5.65 14.13 5.65 1.88 0.02 2.83 (wt%) HMH3 8.0 29.8 19.9 3.6 10.8 4.3 1.4 0.1 2.2 80.0 (mg) 10.00 37.2524.83 4.50 13.50 5.40 1.80 0.02 2.70 (wt %)

This human clinical trial study was a single-center, randomizedcrossover study to evaluate the pharmacokinetic profile of threedifferent HMH formulations (two QD, one BID) of HMH Test CapsulesHMH1-HMH3 against the profile of an IR Control (Dilaudid) oral solutionadministered QID (every 6 hours). There were 15 healthy male subjects ineach study group. One subject dropped out from the IR Control group, soPK results were obtained from 14 subjects for that group only. Subjectswere administered naltrexone blockade to prevent opioid-related adverseevents. Plasma samples were analyzed for hydromorphone using a validatedLC-MS-MS procedure. The results from a pharmacokinetic analysis in thisstudy 9b are reported below in Table 103.

TABLE 103 HMH1 Test HMH2 Test HMH3 Test IR Control Parameter CapsulesCapsules Capsules (Fasted) T_(max) (hr) 6.40 ± 4.31 5.41 ± 2.38 12.13 ±6.45  11.51 ± 7.23  C_(max) (ng/mL) 2.48 ± 0.87 3.14 ± 1.89 3.76 ± 0.946.45 ± 0.99 AUC_(last) (hr*ng/mL) 44.16 ± 20.81 53.78 ± 22.01 74.13 ±17.93 91.95 ± 20.23 AUC_(inf) (hr*ng/mL) 46.94 ± 22.59 59.39 ± 27.1676.45 ± 20.07 96.20 ± 21.09

Example 10 In Vivo Analysis of Formulations

(Human Clinical Trails, Pharmacokinetic Studies)

In order to assess the in vivo controlled release performance ofabuse-resistant hydrocodone oral dosage forms prepared in accordancewith the present invention, the following human clinical trail wascarried out.

The abuse-resistant hydrocodone oral dosage form used in this Example 10was prepared using the following raw materials: Hydrocodone Bitartrate(“HCB”); Isopropyl Myristate, NF (“IPM”); Colloidal silicon dioxide(Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyl toluene, NF (“BHT”);Hydroxyethyl cellulose, NF (“HEC”); Sucrose Acetate Isobutyrate (EastmanChemicals), (“SAM”); Triacetin USP (“TA”); Gelucire 44/14 (Gattefosse)(“GEL”); and Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed(Eastman Chemicals) (“CAB”). The formulations were produced using theGMP manufacturing method of Example 1e above (Process Scheme 9) and thenfilled into size #3 gel cap shells to produce the dosage forms that wereused as Test Capsules. The details of the formulation are disclosedbelow in Table 104.

TABLE 104 HCB SAIB TA CAB IPM HEC SiO₂ BHT GEL Total Formula # (mg) (mg)(mg) (mg) (mg) (mg) (mg) (02 mg) (mg) (mg) HCB1 15.0 41.8 27.8 5.2 14.242.8 1.9 0.1 1.1 110.0 (mg) 13.64 37.97 25.31 4.75 12.95 2.59 1.73 0.021.04 (wt %)

This human clinical trial study was a single-center, randomized,active-controlled crossover study to evaluate the pharmacokineticprofile, as well as describe the effect of food on the rate and extentof absorption of hydrocodone from 15 mg strength abuse-resistant oraldosage forms produced according to the present invention. Subjects wererandomly assigned to one of three treatment groups. The fed treatmentgroup received treatments after an overnight fast of at least 8 hours,followed by thirty minutes after the start of a standard breakfast (8ounces orange juice, two fried eggs, and two slices of toast with butterand preserve). The two fasted groups received treatments after anovernight fast of at least 8 hours. All subjects were administerednaltrexone blockade to prevent opioid-related adverse events. The activecontrol was a 30 mL dose of Lortab Elixir (hydrocodonebitartrate/acetaminophen 7.5 mg/500 mg per 15 mL), “IR Control”. Twentyfour (24) healthy male subjects entered the study, and the PK analysiswas conducted on 22 subjects that completed the study. The plasmasamples were analyzed for hydrocodone using a validated LC-MS-MSprocedure.

The results from a pharmacokinetic analysis in this Example 10b studyare reported below in Table 105.

TABLE 105 HCB Test HCB Test Capsules Capsules IR Control Parameter (Fed)(Fasted) (Fasted) T_(max) (hr) 7.64 ± 2.51 8.37 ± 4.27 1.53 ± 0.66C_(max) (ng/mL) 10.1 ± 5.65 6.62 ± 1.97 37.1 ± 9.53 AUC₀₋₁₂ (hr*ng/mL)68.98 ± 28.65 57.13 ± 18.43 212.1 ± 46.63 AUC_(last) (hr*ng/mL) 178.7 ±69.53 159.0 ± 63.53 259.0 ± 56.77 T_(1/2) (hr) 14.84 ± 8.09  21.11 ±8.31  5.18 ± 0.65

As can be seen by these results, the mean rate and extent of hydrocodoneexposure after administration of the HCB Test Capsules increased underfed conditions relative to fasting conditions. The rate of exposure andpeak of exposure after administration of the HCB Test Capsules was notas high as that seen with the oral hydrocodone elixir (IR Control).

Example 11 In Vivo Analysis of Formulations

(Human Clinical Trails, Pharmacokinetic Studies)

In order to assess the in vivo controlled release performance ofabuse-resistant amphetamine oral dosage forms prepared in accordancewith the present invention, the following human clinical trail wascarried out.

The abuse-resistant amphetamine oral dosage forms used in this Example11 study were prepared using the following raw materials: d-AmphetamineSulfate (Cambrex) (“AMP”); Isopropyl Myristate, NF (“IPM”); Colloidalsilicon dioxide (Cabosil®, Cabot Corp) (“SiO₂”); Butylated hydroxyltoluene, NF (“BHT”); Hydroxyethyl cellulose, NF (“HEC”); Sucrose AcetateIsobutyrate (Eastman Chemicals), (“SAM”); Triacetin USP (“TA”);Cellulose Acetate Butyrate, grade 381-20 BP, ethanol washed (EastmanChemicals) (“CAB”); Caprylocaproyl Polyoxyglycerides (Gattefosse)(“CPG”); Gelucire 50/13 (Gattefosse) (“GEL”); and Polyethylene Glycol8000 (Dow Chemical) (“PEG 8000”). The formulations were produced using aGMP manufacturing process (Process Scheme 6 as described in Example 1aabove) and then filled into size #1 gel capsules to produce the dosageforms that were used as the AMP Test Capsules. The details of theformulations are disclosed below in Tables 106 and 107.

TABLE 106 Formulation by Weight Percent (wt %) Component AMP1 AMP2 AMP3AMP 7.50 5.45 5.45 SAIB 36.52 36.24 35.16 TA 27.05 26.85 26.04 CAB 4.864.96 4.96 IPM 15.73 16.07 16.07 HEC 5.55 5.67 5.67 SiO₂ 1.85 1.89 1.89BHT 0.02 0.02 0.02 LAB 0.93 0 0 PEG 8000 0 2.84 0 GEL 0 0 4.73

TABLE 107 Formulation by Mass (mg) Component AMP1 AMP2 AMP3 AMP 15.0014.99 14.99 SAIB 73.04 99.66 96.69 TA 54.10 73.84 71.61 CAB 9.72 13.6413.64 IPM 31.46 44.19 44.19 HEC 11.10 15.93 15.59 SiO₂ 3.70 5.20 5.20BHT 0.04 0.06 0.06 LAB 1.86 0 0 PEG 8000 0 7.81 0 GEL 0 0 13.01 Total200.02 275.32 274.98

This human clinical trial study was a single-center, randomized,open-label, phase I study to assess the safety and pharmacokinetics ofthree abuse-resistant amphetamine formulations, and to assess theperformance of these Test Capsules against commercially availablereference 15 mg strength controlled release d-amphetamine sulfatetablets (Dexedrine), hereinafter (SR Control) in healthy adult male andfemale volunteers under fed conditions. The study was conducted in 12evaluable healthy subjects. Subjects were administered a single dose ofeach of the four test formulations separated by a minimum of seven days.A standard 4×4 Latin square design was used to assign subjects totreatments. Amphetamine levels were measured in plasma samples using avalidated LC-MS-MS procedure.

The results of the study are depicted in FIG. 33, where the mean plasmaconcentration-time curves of amphetamine are shown. In addition, themean pharmacokinetic values, based on plasma concentration-time values,are presented below in Table 108.

TABLE 108 AMP1 Test AMP2 Test AMP3 Test Reference Capsules CapsulesCapsules Product N 14 15 13 15 C_(max) (ng/mL) 18.1 ± 8.2  21.1 ± 4.8 29.4 ± 5.8  27.8 ± 7.9  t_(max) (hour) 9.4 ± 2.0 7.6 ± 1.5 6.6 ± 1.7 6.3± 1.0 Half Life (hour) 12.8 ± 6.9   12 ± 3.8 9.7 ± 1.9 9.6 ± 1.3AUCt_(i) (hr*ng/mL) 394.3 ± 164.2 474.6 ± 92.5  547.5 ± 114.4 509.4 ±103.6 AUC_(i) (hr*ng/mL) 447.7 ± 164.2 527.0 ± 119.9 575.3 ± 126.3 533.4± 113.7 Relative 83.7 ± 25.4 99.0 ± 17.8 109.0 ± 13.6  Bioavailability

For all PK profiles, an absorption phase lasting approximately 6-7 hourswas evident. This was followed by a distribution phase and anelimination phase. Although all of the test formulations delivered thesame dose of amphetamine, it is noteworthy that the AMP1 Test Capsulesdisplayed the lowest mean profile of all four test formulations, anddisplayed a greater individual variation in amphetamine concentration.

The time course of concentration changes was very similar across the 4treatment groups. Near peak concentrations occur at approximately 6hours for all treatment groups, with maintenance of those near peakconcentrations for approximately another 24 hours. This profile wasconsistent between individuals. There was a tendency for the formulationwith the lowest C_(max) (AMP1 Test Capsules) to display a delayedT_(max). The mean terminal elimination half-life remained consistentregardless of the formulation administered.

Calculation of the relative bioavailability of AMP Test Capsulescompared to a single dose of the 15 mg amphetamine commercial productrevealed that the AMP2 and AMP3 Test Capsules had similar relativebioavailabilities. The relative bioavailability of each of the AMP TestCapsules compared to the SR Control was as follows:

AMP1 (n=14): 83.7±25.4

AMP2 (n=14): 99.0±17.8

AMP3 (n=13): 109.0±13.6.

Although this study was not designed to assess the bioequivalence of theAMP Test Capsule formulations, bioequivalence intervals were constructedfor the ln-transformed ratios of AUC_(t) (Table 109), AUC_(i) (Table110), and C_(max) (Table 111).

TABLE 109 Geometric test-ref Difference Difference CI90 CI90 Ln(AUC_(t))LSM LSM SE Mean difference SE DF lower upper SR Control 6.23 0.06 505.6AMP1 5.91 0.06 368.9 −0.32 0.07 35.00 64.9 82.0 AMP2 6.16 0.06 473.8−0.07 0.07 35.00 83.3 105.4 AMP3 6.32 0.07 555.3 0.09 0.07 35.00 97.3124.0 LSM = Least Square Means SE = Standard Error D-F = Degrees ofFreedom CI90 lower = lower range of the 90% confidence interval CI90upper = upper range of the 90% confidence interval

TABLE 110 Ln(AUC_(t)) Geometric test-ref Difference Difference CI90 CI90formulation LSM LSM SE Mean difference SE DF lower upper SR Control6.2711 0.068 529.0489 AMP1 6.0315 0.0701 416.3577 −0.2395 0.0732 3569.55 89.06 AMP2 6.2616 0.067 524.0704 −0.0095 0.0736 35 87.48 112.17AMP3 6.3717 0.0732 585.0422 0.1006 0.0758 35 97.28 125.71 LSM = LeastSquare Means SE = Standard Error D-F = Degrees of Freedom CI90 lower =lower range of the 90% confidence interval CI90 upper = upper range ofthe 90% confidence interval

TABLE 111 Ln(C_(max)) LSM Geometric test-ref Difference Difference CI90CI90 formulation LSM SE Mean difference SE DF lower upper SR Control3.3005 0.0735 27.127 AMP1 2.7883 0.0767 16.2536 −0.5122 0.0941 35 51.1170.24 AMP2 3.0212 0.0721 20.5151 −0.2794 0.0946 35 64.45 88.74 AMP33.371 0.0814 29.1071 0.0705 0.0975 35 90.99 126.53 LSM = Least SquareMeans SE = Standard Error D-F = Degrees of Freedom CI90 lower = lowerrange of the 90% confidence interval CI90 upper = upper range of the 90%confidence interval

The embodiments disclosed herein are exemplary only, and are not meantto limit the invention, which should be interpreted solely in light ofthe claims.

We claim:
 1. A composition comprising a mixture comprising: amethylphenidate or pharmaceutically acceptable salt thereof; sucroseacetate isobutyrate (SAIB); a cellulose acetate butyrate (CAB);hydroxyethylcellulose (HEC); about 0.01 wt % to about 5 wt % of asaturated polyglycolized glyceride (SPG); and a solvent; wherein themixture is encapsulated within a capsule.
 2. The composition of claim 1,wherein the methylphenidate or a pharmacologically acceptable saltthereof is present in an amount ranging from about 1.3 wt % to about 35wt %.
 3. The composition of claim 1, wherein the SAIB is present in anamount ranging from about 30 wt % to about 60 wt %.
 4. The compositionof claim 1, wherein the CAB has a number average molecular weightranging from about 66,000 to about 83,000.
 5. The composition of claim1, wherein the CAB is present in an amount ranging from about 0.1 wt %to about 20 wt %.
 6. The composition of claim 1, wherein the solvent ispresent in an amount ranging from about 0.1 wt % to about 40 wt %. 7.The composition of claim 1, wherein the mixture further comprises arheology modifier.
 8. The composition of claim 1, wherein the rheologymodifier is present in an amount ranging from about 0.1 wt % to about 20wt %.
 9. The composition of claim 1, wherein the mixture furthercomprises a6silicon dioxide.
 10. The composition of claim 1, wherein themixture comprises methylphenidate.
 11. The composition of claim 1,wherein the mixture comprises a pharmacologically acceptable salt ofmethylphenidate.
 12. The composition of claim 1, wherein the mixturefurther comprises a rheology modifier selected from isopropyl myristate(IPM), caprylic/capric triglyceride, ethyl oleate, triethyl citrate,dimethyl phthalate, and benzyl benzoate.
 13. The composition of claim 1,wherein the capsule comprises gelatin, hydroxyethylcellulose, orhydroxypropylmethylcellulose.
 14. A pharmaceutical dosage formcomprising the composition of claim
 1. 15. The composition of claim 1,wherein the solvent is selected from triacetin, N-methyl-2-pyrrolidone,2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate,and gycofurol.
 16. The composition of claim 1, wherein the solventcomprises triacetin.